Purinoceptors: Ontogeny and Phylogeny Geoffrey Burnstock* Department of Anatomy and Developmental Biology, University College London, London, England

DRUG DEVELOPMENT RESEARCH 39:204-242 (1 996)

Research Overview purinoceptors: Ontogeny and Phylogeny Geoffrey Burnstock* Department of Anatomy and Developmental Biology, University College London, London, England

Venture Capital Preclinical Development Clinical Development Enabling Toxicology, Formulation Phases 1-111 Postmarketing Technology Drug Delivery, Regulatory, Quality, Phase IV Pharmacokinetics Manufacturing

ABSTRACT The majority of studies of the functional distribution of purinoceptors have been carried out with mammalian preparations. The objective of this article is to review the disparate literature describing purinoceptor-mediated effects in invertebrates and lower vertebrates and, in view of the concept that ontogeny repeats phylogeny, to review also the evidence for purinoceptor involvement in the complex signaling involved in embryonic development. Even with the limited information currently available, it is clear that purinoceptors are involved in early signalling in vertebrate embryos; one novel G protein- coupled P2Y receptor has already been cloned and characterized in frog embryo and hopefully more will follow. It is also clear that purinoceptors for both adenosine and ATP are present in early evolution and play a number of different roles in most, if not all, invertebrate and lower species. However, until selective agonists and antagonists are identified for the recently cloned purinoceptors subtypes in vertebrates, it will not be possible to resolve questions concerned with the evolution of these subtypes. Molecular cloning of genes encoding receptors for purines and pyrimidines from invertebrates and lower vertebrates represents an alternative approach to advancing knowledge in the area. Drug Dev. Res. 39:204- 242, 1996. 0 1997 Wiley-Liss, Inc.

Key words: P2 purinoceptors; ATP; ontology; phylogeny

INTRODUCTION surfaces [Cairns-Smith, 19851. In this way, the formation Early Evolutionary Appearance of Purine Nucleotides of ATP from AMP would have paved the way for the formation of oligonucleotides and finally RNA. ATP appears ATP was identified in muscle cells independently to have been particularly suitahle for early development by Fiske and Subharow and by Lohniann in 1929 [see because of its propensity to bond with the metal ion, Mf Schlenk, 1987; Maruyania, IYgl]. 5 '-AMP (myoadenylic that promotes dephosphoiylatiori arid generation of en- acid) was described by Embden and Zimmerman in 1927, ergy; ITP and GTP also show a metal ion-promoted de- but it became clear later that the bulk of 5 '-AMP in cells phosphorylation but their reactive rates arc lower. The occurred as ATP with less than 2% as 5'-AMP per se pyrimidines were also likely to be available in the prinii- [Lohmann and Schuster, 19341. tive earth, but it is suggested that they were incorpo- It has been speculated that the first organisms con- rated into living systenis in ;I more passive way, possibly sisted of RNA arid that as these organisms evolved, they even directed by the purines [Sigel, 19921. Thus, ATP learned to synthesist: proteins which could help them to appears to have played a crucial and activc role in early replicatc more cfficicntly; later, RNA-based organisms evolution. In contemporary biochemistry, ATP is still the gave rise to DNA, a molecule more reliable for storing most important energy-rich intermediate in nucleotitle the genetic information [Waldrop, 1989; Horgan, 19911. processes. The cnzyme-catalyzed hydrolysis of ATP to Phosphorylation of nucleosides and the formation of pyrophosphate bonds may have occurred on the early earth by purely theriiial processes [Sawai and Orgel, 19751, the *Correspondence to: Professor C. Burnstock, Department of resulting compounds becoming important starting nia- Anatomy and Developmental Biology, University College London, terials for further syntheses in aqueous solutions or on Cower Street, London WC1 E GBT, England.

0 1997 Wiley-Liss, Inc. ONTOGENY AND PHYLOGENY OF PURINOCEPTORS 205

ADP and PO4 is the main source of cncrgy. It has been times or more in Bacillus subtilis [Murao et d., 1980; estimated that ATP participates in more chemical reac- Kameda et al., 19831 and Streptornyces galilaeus tions than any other compound on the earth's surface, [Hamagishi et al., 19801. Extracellular ATP and other 5 '- except water. nucleotides are broken down by the high activity of mem- Compelling arguments have been presented for the brane-bound 5 '-nucleotidase in the halophilic bacterium, prominent role of ATP and ADP in intracellular energy Vibrio costicole [Sakai et al., 19871. UTE ATE and pyro- metabolism very early in evolution, including the: avail- phosphate are metabolized by alkylsulfatase-producing ability of adenine compounds in the biosphere and the bacteria [Stewart and Fitzgerald, 19811. Membrane-as- development of complementary binding sites on cellular sociated ATPases from halophilic archaebacterium in- proteins [see Wilson, 19841. However, until recently, less cluding Holobacterium salinarium and Methanosarcina attention has been directed towards the early evolution- harkeri have been isolated, purified, cloned, and sequenced ary appearance of ATP and adenosine as extracellular [Ihara and Mukohata, 19911. TmrB protein, responsible for messengers in cell communication and signalling. tunicamycin resistance of Bacillus suhtilis, is a novel ATP- In the evolution of neurochemical transmitters it binding membrane protein [Noda et al., 19921. has been suggested that purine derivativcs may well have been the primordial transmitter substances [Trams, 19811. History and Current Perception of Extracellular There are reports of extracellular actions of ATP in very Purinergic Signalling primitive organisms, including bacteria, diatoms, algae, Since the early recognition of the potent extracel- and slime moulds. For example, ATP inhibits prodigi- lular actions of ATP and adenosine by Druiy and Szent- osin formation in Serratia rnarcescens, while adenosine Gyorgyi [1929]there has been an escalating development does not [Lawanson and Sholeye, 19761. Exogenous ATP of knowledge of the receptors involved. In 1978, Burn- stimulates generative nuclear division in pollen tubes of stock established the existence of separate receptors for Lilium longiflorum [Kamizyo and Tanaka, 19821. ATP adenosine (Pl)and for ATP/ADP (P2) and subclasses of regulation of oscillating torsional movement in strands P1 receptors (A, and A,) [Londos et al., 19801 and for P2 of the slime mould Physarum polycephalum has also been purinoceptors (P2X and P2Y) [Burnstock and Kennedy, described [Ogihara, 19821. Caffeine, an adenosine antago- 19851 followed. P1 purinoceptors have been long known nist, can block cell plate formation in nieristem cells of to act via adenylate cyclase second messenger systems onion root tips arid adenosine antagoriises this action [Sattin and Rall, 19701. On the basis of the transduction [Gonzalez-Fernandez and Lopez-Saez, 19801. Changes mechanisms involved in PZ-purinoceptor activation in membrane potential and excitability of Cham ccds and [Dubyak, 19911 and cloning of the receptors [Webb et cytoplasmic streaming in response to ATP have been al., 1993; Lustig et al., 1993; Valera et al., 1994; Brake et demonstrated [Williamson, 1975; Shimmen and Tazawa, al., 19941, Ahbracchio and Burnstock [1994] outlined the 19771. Both adenosine and 2 '-deoxyadenosine at very basis for the currently accepted subclassification of P2 low concentrations M) promoted growth in the dia- purinoceptors, namely the subdivision into a P2X family tom Phueodactylzim tricornutum [Komacla et al., 19831.A of ligand-gated ion channel receptors and a P2Y family high affinity binding site for ATP has been localised on of G protein-coupled receptors. To date, seven meniliers membrane-bound chloroplast ATP synthase isolated from of the P2X purinoceptor family and eight members of leaves of spinach [Abbott et al., 19841. The F,-ATPase the P2Y purinoceptor family have been recognized [see component of ATP synthase from chloroplasts (as well as Burnstock, 1996a; Burnstock and King, 19961. mitochondria and microorganisms) contain six sites that The majority of studies of purinoceptor functional can be occupied by adenine nucleotides [Senior, 19881. distribution have been carried out in mamrnalian prepa- Adenosine has been shown to inhibit the growth of vari- rations and it is one objective of this article to review the ous bacteria including Crithidia fasciculata [Dewey et disparate literature describing purinoceptors in inverte- al., 19781,Micrococcus sodonensis [Shobe and Campbell, brates and lower vertebrates firstly to establish the primi- 1973a,b], and Staphylococcus aureus [Matheiu et al., tive and long-standing utilization of these receptors 19691. Adenosine polyphosphates have been found in during evolution and secondly to see if any pattern of bacilli [Rhaese et al., 19721 and in Streptornyces [Muraio receptor subtype development can be recognized. et al., 19781 and have been considered to be involved in In view of the extraordinarily widespread distribu- the initiation of sporulation in Baccillis subtilis [Rhaese tion of extracellular receptors for purines during phylog- et al., 19721. Some purine and pyrimidine nucleotides eny, the second objective of this article is to review the and nucleosides inhibit spore germination in Streptorny- beginnings of exploration into possible roles for purines ces galilaeus [Hamagishi et al., 19801. Exogenous adenos- during the complex sequences of signalling involved in ine 5 '-triphosphate 3 '-diphosphate (pppApp) reduces embryonic development. The article will not include growth rate and increases sporulation frequency by 100 descriptions of the postnatal development of purinocep- 206 BU RNSTOCK tors or changes occurring in aging, but some accounts ing Xenopus neuromuscular synapses in culture potenti- are available [see Swedin, 1972; MacDonald and ate ACh responses of developing muscle cells during the McGrath, 1984; Furukawa and Noinoto, 1989; Matherne early phase of synaptogenesis [!A and Poo, 1991; Fu, 1994; et al., 1990; Koga et al., 1992; Nicholls et al., 1992; Fu and Huang, 19941. The possibility that extracellular Zagorodnyuk et al., 1993; Peachey et al., 19961. ATP co-released with ACh, may serve as a positive trophic It is important to recognize that both short-term factor at developing neuromuscular synapses has also signalling, such as that occurring in neurotransmis- been raised [Fu and Poo, 1991; Fu; 19951. It is further sion and secretion [see Burnstock, 1972, 1996111 and suggested that calcitoniii gene-related peptide (CGRP) long-term signalling involved in cell division, prolif- and ATP co-released with ACh from the nerve terminal eration, differentiation, regeneration, and death and may act together to potentiate postsynaptic ACh channel in plasticity of expression in pathological states includ- activity during the early phase of syriaptogenesis [Lu and ing wound healing [see Fraser et al., 1979; Ziada et Fu, 19951; it is claimed that CGRP actions are mediated a]., 1984; Teuscher and Weidlich, 1985; Dusseau et by CAMP-dependent protein kinasc (PKA), while ATP a]., 1986; Meininger et al., 1988; Adair et a]., 1989; exerts its effects via protein kinase C (PKC). Huang et a]., 1989; K~ibo,1991~; Rathbone et al., 1992; In a recent study of the regulation of rhythmic Erlinge et a]., 1993; Henning et al., 1993a,b; movements by purinergic transmitters in frog embryos Burnstock, 1993; Abhracchio et al., 1994; Boarder et [Dale and Gildry, 19961, it has been shown that ATP is al., 1995; Neary ct al., 1996; Abbracchio, 19961 should released during swimming that activates P2Y-receptors be taken into consideration when examining both the to reduce voltage-gated K+ currents and cause an increase ontogeny and phylogeny of purinoceptors. in the excitability of the spinal motor circuits. It was also shown that adenosine, resulting from the breakdown of ONTOCENY OF PURINOCEPTORS ATE acts on P1 receptors to reducc the voltage-gated In the past, a role of ATP in early development has ca2+currents to lower excitability of the motor circuits been interpreted merely in terms of its use as a source of thereby opposing the actions of ATE The authors sug- energy. However, since it is now generally accepted that gest that a gradually changing balance between ATP and ATP and adenosine have potent extracellular actions adenosine underlies the run-down of the motor pattern mediated by the activation of specific membrane recep- for swimming in Xenopus. tors, a number of these previous studies can now be re- We have recently cloned arid sequenced in m~7lah- interpreted. ATP and adenosine play key roles from the ratory a novel P2Y-purinoceptor (X1P2Y) that is expressed very beginnings of life, i.e., the moment of conception. (as seen by Northern blots and in situ hybridization) in ATP is obligatory for sperm movement [Yeung, 19861 and the neural plate ofXenopus embryos from stages 13 to 18 is a trigger for capacitation, the acrosome reaction nec- and again at stage 28 when secondary neurulation oc- essary to fertilize the egg [Foresta et al., 19921. Extracel- curs in the tail hud [Bogdanov et al., 19971. It differs from liilar ATP also promotes a rapid increase in Na' other members of the P2Y-purinoceptor family in that it permeability of the fertilized egg membrane through the has an intracellular C terminus with 216 amino acid resi- activation of a specific ATP receptor [Kupitz and Atlas, dues (compared to 16 to 67 in P2Y1-?).When expressed 19931. Together with the demonstration that ATP-acti- as a recombinant receptor in Xenopus oocytcs, it shows vated spermatozoa show very high success ratcs in fer- equipotent responses to the triphospliates ATE: UTE ITe tilization tests [Foresta et al., 19921, this strongly suggests CTE and GTP and smaller responses to diphosphates and that ATP is a key sperm-to-egg signal in the process of tetraphosphates, but is not responsive to inorganic phos- fertiliz at' ion. phates. Responses to activation of the XlP2Y receptor have a long duration (40-60 min). These data suggest that Purinoceptors in Frog Embryos this novel PZY-receptor may he involved in the early for- The nicotinic channels in myotomal muscle cells mation of the nervous system. cultured from Xenopus embryos at stages 19-22 were shown to be opened by micromolar concentrations of Purinoceptors in Chick Embryos exogenous ATP [Igusa, 19881, following the earlier dem- Together with muscarinic cholinergic receptors, onstration that ATP increases the sensitivity of receptors extracellular receptors to KrP were shown to he the first in adrilt frog skeletal muscles without increasing the af- functionally active membrane rceeptors in chick embyo finity of acetylcholine (ACh) for the receptor or inhibi- cells at the time of germ layer formation [Laasherg, 19901. tory acetylcholinesterase [Akasu et al., 19811. Since then, In gastrulating chick embryo, ATP causes rapid accumii- there have been a number of studies of the actions of lation of inositol-phosphate and Ca" mo1)ilization in a ATP in developing Xenqms neuroinuscuku synapses [see similar way and to the same extent as ACh, whereas othcr Fu, 19951. Extracellular applications of ATP to develop- neuroendocrine substances such as insulin and noratf- ONTOGENY AND PHYLOGENY OF PURINOCEPTORS 207 renaline (NA) have much weaker effects [Laasberg, 19901. purinoceptors and that there is a dramatic decline of the This suggests that, alongside ACh, other phylogenetically ATP-induced rise in intracellular Ca2+just before old and universal regulators of cell metabolism such as synaptogenesis. Suramin and Reactive Blue 2 almost com- ATP (and perhaps nitric oxide) might play a leading role pletely block these responses (Fig. 2). These authors also in the functional regulation of gastrulation via the activa- reported unpublished data that injection of Reactive Blue tion of specific receptors triggering CaZ+mobilization. 2 into early embryonic chicks produced severe effects in ATP has been shown to induce precocious evagi- embryogenesis. nation of the embryonic chick thyroid, an event which A transmitter-like action of ATP on patched niem- has been hypothesized to be involved in the formation of branes of myoblasts and myotubes cultured from 12-clay- the thyroid gland from the thyroid primordium [Hilfer old chicken embryos was first demonstrated by Koll) and et al., 19771. The requirement for ATP was very precise, Wakelam in 1983. Using biochemical methods, ATP-in- since it could not be replaced by pyrophosphate, AME duced cation influx was later demonstrated in rnyotubes or ADP nor by GTI: suggesting a high degree of specific- prepared from 1l-day-old chick embryos and shown to ity of the ATP-induced effect. be additive to cholinergic agonist action [Hiiggblad ct al., ATP acts on embryonic and developing cells of both 19851. Later papers from this group claimed that the nervous and non-nervous systems by increasing intrac- myotube P2-purinoceptor triggers phosphoinositideturn- ellular Ca2+concentrations. Release of Caz+from intrac- over [Hiiggblad and Heilbronn, 19881 and alters Ca" in- ellular stores is evoked in the otocyst epithelium of the flux through dihydropyridine-sensitive channels [ Erikson early embryonic chick, incubated for 3 days (stage 18 to and Heilbronn, 19891. ATP has a potent dcpolarizing ac- 19) [Nakaoka and Yamashita, 19951 (Fig. l),in develop- tion on myotubes derived from pectoral muscle cultured ing chick myotubes [Haggblad and Heilbronn, 1088] and from 11 day chick embryos [Hume and Hiinig, 19861 and in dissociated cells from whole early embryonic chicks its physiological and pharmacological properties have [Laasberg, 1990; Lohmann et al., 19911. been described in a series of papers [Hume and Thomas, A recent study of embryonic chick neural retina 1988; Thomas and Hume, 1990a,b, 1993; Thomas ct al., [Sugioka et al., 19961 has shown that the ATP-induced 19911. The niyotube P2-purinoceptor is not activated by rise in intracellular Ca2+is mediated by PZu(= P2Y2)- ADE AME adenosine or the non-hydrolyzable ATP analogues a,P-methylene ATP (a,P-meATP) or P,y-methyl- a 1OuM ACh ene ATP (P,y-meATP)[Hume and Hiinig, 19861. A single '- class of ATP-activated ion channel conducts both cations *.O I$".,--and anions in the myotube [Thomas and Hume, 1990al and the P2-purinoceptors involved showcd marked dc- sensitization [Thomas and Hume, 199ObI. The sensitivity of extracellular ATP has been tested at various stages of development of different muscles [Wells et al., 19951. At embryonic day 6 [stage 30 of Hamberger and Hamil- ton, 19511 ATP (50-lOOpM) elicits vigorous contractions in all the muscles tested, but by embryonic day 17 (stage 43) none of the muscles contract in response to ATP (Fig. 3). However, denencation of muscles in newly hatched 10pM ACh+l OOpM AT? chicks leads to the reappearance of sensitivity to ATE C --~~ 2.5 t -1 suggesting that the expression of ATP receptors is regulated by motor neurons. An immunohistochemical study 4 of the distribution of 5 '-nucleotidase during the development of chick striated muscle shows that the adult exhibits a more restricted distribution compared to the einbryo [Mehul et al., 19923. Studies of the development of pharmacological sen- 0- 80s sitivity to adenosine analogs in embryonic chick heart [Hatae et al., 1989; Blair et al., 19891 show that pharma- Fig. 1. Interaction between acetylcholine and A-IP recorded in an oto- cological sensitivity to Al agonists begins at embryonic cyst from chick embryo. a: The response to 10 pM acetylcholine. b: The day 7 and then increases continuously to day 12, when response to 100bM ATP. C: The response to the co-application of 10p.M acetylcholine and 100 p.M ATP. The records in a-c were taken in this the atria became fully responsive. Ligand binding shows order at 5 min intervals. The bath solutions contained 25 rnM Ca". Re- that A, receptors are present at days 5 and 6, but are not produced from Nakaoka and Yamashita, 1995. responsive to adenosine, and the author concluded that 208 BURNSTOCK Aa Ba I

90 LLO I 100 IIM suramin

1 .o 1 0 Time (s) 80 0 Time (s) 80 200 p~ UTP 500 pM ATP b b

Wash

1.o 0 Time (s) 80 0 Time (s) 80 500 ,UM ATP 200 pM UTP

Fig. 2. Effects of P2 purinoceptor antagonists on the Ca2+ responses to mMCa2+.6: The effects of suramin (100 pM; B,a) and Reactive Blue 2 ATP and UTP in E3 retinas. A: The effects of ~uramin(100 pM; A,a) and (50 pM; B,b) on the response to 200 pM UTP. The records in the pres- reactive blue 2 (50~M;A,b) on the response lo 50UpM ATP. The records ence of suramin or Reactive Blue were taken 7 min after changing the in the presence of suramin or Reactive Blue 2 were taken 7 min after bath solutions to the antagonist-containing medium. The recovery con- changing the bath solutions to the antagonist-containing medium. The trols were taken after washingsuramin for 7 min or reactive blue 2 for 15 recovery controls were taken after washing suramin for 7 rnin or reactive min. The duration of UTP application (20 s) is indicated by the bars. All blue 2 for 25 min. The duration of ATP application (20 s) is indicated by records were taken in the bath solutions containing 2.5 mM Ca2+. Re- the bars. All records were taken in the bath solutions containing 2.5 produced from Sugioka et al., 1996. the development of sensitivity to Al adenosine receptor- antagonist (Fig. 4). The authors suggest that the P2 recep- mediated negative chronotropic responses was not par- tor subtype involved might be PBY, but in view of more alleled by developmental changes in adenosine inhibition recent knowledge about the functional properties of cloned of adenylyl cyclase, or hy the devcloprnent of sympathetic subtypes of the P2 receptor family, it seems more likely to and parasympathetic innervation. Chronic exposure of belong to the P2X receptor family. the enibryonic chick heart (15-17-days-old) to R-PIA Adenosine inhibits neurite outgrowth of chick sym- produces down-regulation of Al adenosine receptor and pathetic neurons taken from 11 day chick embryos and kills desensitization of the negative inotropic response to ad- by apoptosis about 80% of sympathetic nerves supported enosine [Shryock et al., 19891. by growth factor over the next 2 days in culture [Wakade et Adenosine has been iniplicated in growth regula- al., 19951. Specific Al or A2 agonists are not neurotoxic. The tion of the vascular system in the chick embryo [Adair et toxic effects of adenosine are not antagonized by amino- al., 19891, in common with a similar role claimed for ex- phylline, but are prevented by an adenosine transporter or perimental angiogenesis in the chorio-allantoic nxm- adenosine deaminase inhibitor, suggesting an intracellular brarie [Fraser ct al., 1979; Teusher and Weidlich, 1985; site of action for the toxic effects of adenosine. The authors Dusseau et al., 19861. conclude that adenosinc and its breakdown enzymes play Responses to ATP have heen described in ciliary neu- an important role in the regulation of growth and devclop- rons acutely dissociated horn embryonic chick ciliary gan- nient of sympathetic neurons. glia taken at day 14 [Abe et al., 19951. The relative potency of agonists in producing transicnt inward currents with Purinoceptors in Mammalian Embryos patch recording is ATP>2meSATP>ADP; neither adenos- Puff-applied ATP has been shown to have two main ine, AMP or a,P-meATP are effective, but suramin is an effects on a mouse mesodermal stem cell line: an increase ONTOCENY AND PHYLOGENY OF PURINOCEPTORS 209

VENTRAL DORSAL

PATAGIALIS LONGUS . ANTERIOR LATISSIMUS WRSl EXTENSOR CARPI RADIALIS \

LNARIS LATERALIS FLEXOR CARPI RADlALIS TRICEPS BRACHll TRICEPS LONGUS POSTERIOR LATISSIMUS DORSl PECTORALS SUPERFlClA SARTORlUS PECTORALIS SUBCLAVIS / I

TENSOR FASCIA LATAE

~ BICEPS FEMORIS

Fig. 3. Location of the muscles of the chick embryo that were respon- bryos. All muscles tested in embryos of these ages contracted in response sive to ATP. Three chick embryos from stages 35-37 were sacrificed, and to ATP. By embryo day 17 (stage 43) none of the muscles contracted in each muscle was identified and tested in at least two of the three em- response to ATP. Reproduced from Wells et al., 1995. in intracellular Caz+ concentrations and a subsequent ine as one of the endogenous effectors that can selectively hyperpolarization due to Ca2+-activatedKt conductance modulate cell growth during embryonic development. For [Kubo, 1991aI (Fig. 5).The author speculates that the tran- example, adenosine is shown to potentiate the delaying sient increase in intracellular ca2+may influence meso- effect of dibutyryl cyclic adenosine monophosphate (a dermal cell differcntiation, particularly in relation to membrane-permeable analog of CAMP) on meiosis re- muscle differentiation. In a later paper [Kubo, 1991b], sumption in denuded mouse oocytes [Petrungaro et al., two myoblastic cell lines, one from rat, the other from 19861. The role of adenosine has becn particularly well mouse, showed similar properties to those of the myo- characterized in the morphogenetic outgrowth of verte- genic clonal cells derived from the muuse mesodermal brate limb buds [Knudsen and Elmer, 19871. Embryonic stem cell line described above. limb development in the mouse is driven by rapid rnes- ATP and ADP have been shown to enhance, re- enchymal cell proliferation induced by trophic substances duce, or have no effect (depending on the dose used) on secreted by the apical ectodermal ridge. This interaction the incidence of trypan blue-induced teratogenic mal- can be restricted experimentally by pharmacological formations in the rat foetus at day 20 [Beaudoin, 19761. agents that elevate intracellular CAMP levels, or physi- Concomitant administration of ATP and cortisone in mice ologically by the onset of programmed cell death trig- either decrease the teratogenic effect of cortisone (SO pg gered by naturally occurring negative regulators of ATP) or enhance its teratogenic effect (>lo0 pg ATP) growth. Mutations that affect the pattern of limb/bud [Gordon et al., 19631. outgrowth provide invaluable experimental means to in- Mouse heads of emhyos from 14 to 24 pairs ofbody vestigate these growth-regulatory processes. Knudsen somites exposed to an ATP-containing medium have been and Elmer [1987] studied the regulation of polydacty- demonstrated to undergo rapid epithelial thickening and lous out growth (an expression of the Heinimelia-extra invagination, a process that appears to take part in the toe (HmX/+) mutant phenotype) in hind-limb buds ex- shaping of nasal pits and formation of' primary palate planted into a serum-free in vitro system at stage 18 of [Smuts, 19811. gestation. Its expression was promoted by exposure to Besides ATE: a number of reports implicate adenos- exogenous adenosine-deaminase, the enzyme which cata- 21 0 BU RNSTOCK

100pM ATP 10 pM I n -

1 ? 10s

0.1 1 10 100 Surarnin @M)

Fig. 4. Chick embryo (day 14) ciliary ganglion cells: the inhibition of ATP and suramin, respectively. In the lower panel, the responses in the ATP-induced inward current by suramin. The neurons were pretreated presence of suramin are normalised to the peak current amplitude in- with suramin of various concentrations for 2 min. In the upper panel, duced by 10 pM alone. Each point is the average of four neurons, and the filled and open horizontal bars indicate the periods of application of the vertical bars indicate S.E.M. Reproduced from Abe et al., 1995. lyzes the inactivation of endogenous adenosine, and con- tion and are no longer sensitive by 34 h [Loutradis et al., versely suppressed by co-exposure to hydrolysis-resis- 19891. However, a later study by this group has shown tant adenosine analogues. Adenosine-induced effects that the purine-induced block can be reversed by com- were niediated by activation of specific extracellular re- pounds that elevate CAMP [Fissore et al., 19921. ceptors, since the Pl-purinoceptor antagonist, caffeine, In a study of human fibroblasts, differential sensi- could completely prevent suppression of polydactylous tivity to adenosine was demonstrated in donors of dif- outgrowth. Measurenient of both adenosine and adenos- ferent ages !Bynum, 19801. Fetal fibroblasts were the ine deaminase levels in embryonal plasma and whole em- most sensitive to adenosine, which produced inhibition bryos argued against an endocrine mechanism of adenosine of growth and RNA synthesis; in contrast, fibroblasts secretion, in favour of an autocrine (self-regulatory) or taken from 4-year-old donors showed growth stiniula- paracrine (groximate-regulatorymechanisms). These results tion to adenosine. suggest that the in vitro outgrowth of the prospective poly- Taken together, these results point to a role for pu- dactylous region is induced upon escape from the local rines in both physiological fertilization and normal de- gowth-inhibitory influence of extracellular adenosine. velopment and also underline that alterations of the Micromolar concentrations of adenosine, inosinc, purinergic regulation of embryonal growth might be in- and hypoxanthine, but not guanosine block the second volved in the onset of morphological malformations. or third cleavage of niousc embryos developing in vitro Depending upon the purine derivative, and probably [Nureddin et al., 19901. Zygotes or early two-cell em- upon the purinoceptor involved as well, ATP and adenos- bryos, cultured in a purine-containing medium for 24 h, ine can act as both positive and negative regulators of resume development following transfer to purine-free growth. This is also consistent with data obtained from conditions. The precise mechanism of the purine-sensi- in vitro cell lines which implicates purines in both cell tive process is not known, hut embryos coiiceivcd in vivo proliferation and apoptosis. Further studies are needed are sensitivc until approximately 28-30 h after fertiliza- to better characterize the receptor subtypes involved and ONTOGENY AND PHYLOGENY OF PURINOCEPTORS 21 1

ATP A later electron microscopic study by the same group has suggested that synapse-bound 5 '-nucleotidase activity plays a role in synaptic malleability during develop- 'A I ment; its later association with glial cell profiles may -- reflect other functions for this enzyme [Schocn et al., lo 5 19933. Complex changes in the activity of adenosine AMP deaminase in the different regions of the developing rat brain suggest that there are important roles for purines in very early stages of development from 1.5 days of gestation, as well as in the adult in specific regions of the brain [Geiger and Nagy, 1987; Senba et a]., 19871. A his- Adenosine C I tochemical study of Ca2+-ATPasein the rat spinal cord P during embryonic development demonstrated intense

ATP- y-S activity in the roof and floor plates, rather than in the basal and lateral plates at embryonic day 12, indicating a possible role for Ca2+-ATPasein early differentiation of neuroepithelial cells [Yoshioka et al., 19871.ATP induces rises in intracellular Ca2+ in embryonic spinal cord astrocytes [Salter and Hicks, 19951. In foetal sheep, centrally administered adenosine influences cardiac function [Egerman et al., 19931. The ontogeny of Al adenosine receptors was studied in rats with binding assays (using [3H]DPCPX,an Al antagonist), and by in situ hybridization of mRNA [Rivkees, 19951. At Fig. 5. K+ responses to ATP analogues of a mouse mesodermal cell gestational days 8-11, mRNA expression for A, receptor line. Each of the two traces was obtained from the same cell (A-E). The responses induced by ATP (left traces) and ATP analogues (right traces) was detected in the atrium (one of the earliest G protein- are shown. The names of the analogues are shown near the traces. Each coupled receptor genes to be expressed in the heart),but drug was applied at 20 pM, and the holding potentials were 0 mV. Re- not in other foetal structures, while at gestational day 14, produced from Kubo, 1991a. A, mRNA was present in the CNS (thalamus, ventral horn of spinal cord) as well as the atrium; by gestational age also to identify more precisely the developmental events 17, patterns of Al receptor expression in the brain were specifically controlled by purines. similar to those observed in adults [Weber et al., 1990; Radioligand binding studies have provided infor- Reppert et al., 19911. Determination of A, receptor den- mation about the development of Al receptors in guinea- sity in developing rat heart using ['HIDPCPX, showed pig and rat brain, in particular the forebrain and that functional Al receptors are present in greater nuni- cerebellum [Morgan et al., 1987, 19901. In guinea-pig hers in the immature perinatal heart than in the adult forebrain it appears that A, receptors are present from heart [Cothran et al., 19951. embryonic day 19, with adult binding levels achieved Intravenous infusion of adenosine analogs into foe- about 25 days postpartum. In guinea-pig cerebellum, tal lambs produced dose-dependent bradycardia arid however, Al receptor binding is low until just prior to hypotension [Yoneyama and Power, 19%; Kondiiri et al., birth, when a dramatic increase in binding is observed 1992; Koos et al., 19931. In contrast, in the newborn, which then continues to increase up to adulthood. A simi- NECA produced dose-dependent tachycardia, while PIA lar development is seen in rat forebrain and cerebellum and CHA produced dose-dependent bradycardia. Foetal with Al receptor binding changing very gradually in the breathing movements were interrupted by all analogs, forebrain, whereas binding in the cerebellum increases but they did not produce apnea in the newborn [Toubas markedly after birth [Marangos et al., 1982; Geiger et et al., 19901. al., 19841. In the gastrointestinal tract, responses to ATP have There are a number of reports about changes in the been observed in rat duodenum the day after birth, sug- distribution of the ectoenzymes involved in the break- gesting that functional P2-purinoceptors are present at down of ATP and adenosine in the brain during foetal this time. Low concentrations of ATP were inhibitory at and neonatal development. 5 '-Nucleotidase shows a every age studied and its potency increased with age, marked redistribution during development of the cat vi- while higher concentrations were excitatory but only until sual cortex and is thought to be involved in the remodel- 15 days after birth [Nicholls et al., 19921. It has been pro- ling of ocular dominance columns [Schoen et al., 19901. posed that ATP is a non-adrenergic, non-cholinergic 21 2 BURNSTOCK

(NANC) rieurotrarisrriitter in riiany areas of the gas- variety of different invertebrate and lower vertebrate tis- trointestinal tract [Burnstock, 19721 and NANC neive- sues, to attempt to characterize purinoceptor subtypes, mediated effects have been ohserved before hirth in rat and to consider thcsc findings in evolutionary terms. stomach [Ito et al., 19881 and in inwise and rabbit small Invertebrates intestine [Cershon and Thompson, 19731. Also, quinacrine fluorescence, which indicates the presence of high Protozoa levels of bound ATP in nerves, is observed before birth The inhibitory effects of external ATP on amoeboid in ral,bit ileum and stomach [Crowe and Bunistock, 19811. movement has been recognized for many years [Zimmer- ATP has also been proposed as the non-cholinergic man ct al., 1958; Zimmerman, 1962; Nachmias, 19681. excitatory transmitter in urinary bladder [ Burnstock et Output from the contractile vacuole of Amoebu protei~s al., 1978a,b] aiid purinergic responses are apparent at increases in the presence of ATP and, to a lesser extent, birth [Keating et al., 19901. Purincrgic innervation and other polyphosphates [Pothier et al., 1984, 1987; responsiveness to ATP is greater in 1-day-old urinary Couillard, 19861. Amoeba behaves as an excitable cell; bladder than in adult tissue [Keating et al., 1990; Zderic its membrane responds to KI'P by iion-propagated last- et al., 1990; Snccldon arid McLees, 19921. The inipor- ing depolarizations, probably resulting from opening of tance of ATP in neonatal tissue has also been demon- sodium channels. Cell-surface receptors for adenosine strated in rat vas tleferens, where ATPhas heen proposed and cyclic adenosine 3 ' ,5' -monophosphate have been as the cotransmitter with NA in sympathetic nerves reported in the free-living amoeba of the slime mould, [Meldrum and Burnstock, 19831. Dict!yosteliuin discoideuin; they niediate signals involved Purinoceptors have been characterized in iiiousc in cell aggregation [Robertson et al., 1972; Clark and C2C12 myotubes [Henning et al., 1992,1993a,b].Adenos- Steck, 1979; Newell, 1982; Ncwcll and Ross, 19821. ine-sensitive P1-purinoceptors activating cyclic AMP Externally applied, CTP alters the motility and elic- formation were identified and a novel PZ-purinoceptor its an oscillating membrane depolarization in Purmecium was also postulated, sensitive to ATE ADT: and ATPyS, tetrcieiureliu, a unicellular ciliated protist [Clark et al., which also activates the formation of CAME This recep- 19931. More specificaIly, it transiently induces alternat- tor was also sensitive to UTE but not a,P-meATE 2nieSATE ing forward and backward swimming interspersed with GTE or CTE: thus reseinbling the P2Y2 (= P2u)-purinocep- whirling at a concentration as low as 100 nM. ATP is tor identified in mainmals. The response to ATP and U'TP 1,OOO-fold less active, while CTP and UTP are virtually was biphasic, a transient hypeipolarization being followed inactive. The authors suggest that GTP released from by a slowly declining clcpolarization; the li?i~e'l,olarization lyscd paramecia, brought on by predators or noxious was blocked by apamin arid surariiin arid abolished under chemicals, may be used as a signal to ncighbouring para- Ci"-free conditions. Occupation ofthe receptor by ATP mecia to evacuate the local area. ATP is known to alter or UTP led to formation of inositol trisphosphate and the rate of beat of cilia in Purcimeciurn and it is interest- release of ~2'from internal stores as well as from the ing that there are lower levels of adenosine triphosphasc extracellular space. in slow-swirnniirig niutants [Hayashi and Takahashi, 19793. As for Amoeba, ATP has also ken shown to increase the PHYLOGENY OF PURINOCEPTORS rate of output of contractile vacuoles in Pclrurneciziin [Or- While there have been some commentaries and gan et al., 19681. The ecto-ATPase from the ciliary mem- reviews about the evolution of transniitters (including branes of Pcwumeciurn is similar to that from mammalian acetylcholine, rnonamines, amino acids, peptides, and brain and the cndothclial plasnia nicmbrane with respect nitric oxide), their receptors and ion channels [Venter et to kinetics, ionic requirements, and insensitivity to vana- al., 1988; Walker and Holden-Dye, 1989, 1991; Messen- date [Doughty and Kaiieshiro, 19851. ATP keeps exocyto- ger, 1991; Arbas et al., 1991; Feelisch and Martin, 19953, sis sites in Paramecium in aprimed state, but is not required few have referred to receptors for purines. There is now for membrane fusion [Vilmai-t-Seuwen et al., 19861. a wealth of infimtiatioii about the distribution of pu- ATP causes herniation (blebbiiig) and plasmodia1 rinoceptors in mammalian tissues, although there have disruption of the myxomycete Phys~irurnpolgcephcilutn been some reports of the extracellular roles of purine [Mante et al., 19781; the authors suggest that these ef- nucleosides and nucleotides in invertebrate and lower fects may reflect acceleration of normal contractile pro- verte1)rate species [scc Burnstock, 1975, 1977, 1979; c e s s e s in this organism. U s in g 1u c i fe ri n - 1u ci fe ras e Berlind, 1977; Siebenallcr and MLI~XL)~,1986; Venter et I~iolu~ninescciicc,ATP has bcen shown to lcak out rhyth- al., 1988; IIoylc and Greenberg, 1988; Walker and mically from Physarzm and tlic period and phase of os- Holden-Dye, 1989; Feng and Doolittle, 1990; Linden et cillation in ATP leakage corresponds well with those of al., 19941. It is the aim of this section to review what is tension production [Yoshimoto et al., 1981; Uyeda and known abut the actions ofl)oth adenosine and ATP on a Furuya, 19871. Extracellular ATP leads to changes in the ONTOGENY AND PHYLOGENY OF PURINOCEPTORS 21 3 cytoskeletal organisation in Physarum apparently caus- ganglia and ventral nerve chord, with nerve cclls along ing the microtubules and microfilaments to slide apart the length of the chord not necessarily confined within [Uyeda and Furnya, 19871. ganglia and with peripheral nerves from each segment. Certain adenosine analogs have been shown to in- Electrophysiological investigations, using lmth inhibit the growth of Giurdia Zurnblia, a protozoan parasite tracelliilar rnicroelectrodes and whole cell patch-clamp that canses diarrhoea in both man and animals; dnig treat- recording on identified neurones in the central nervous ment includes the use of quinacrine, which is known to system of the leech Hirudo medicinalis revealed that A'I'P bind high levels ofATP [see Berens and Marr, 19861. Both and ADP depolarised selected neurons but not the neu- adenosine and 2 '-deoxyadenosine are inhibitory to the ropil glial cells [Backus et al., 19941 ('Iablc 1).The most growth of the trypanosome protozoon Crithidia effective responses (up to 10 mv) were ohserved in the fusculuta; this inhibition of growth is reversed by py- noxious and touch cells. In most neurons the stable ana- rimidine nucleosides [Dewey et al., 19781. Trypano- log of ATE ATP-y-S (5 pM) induced larger depolariza- soma hrucei is the causative agent of sleeping sickness tions than ATE: indicating that ectonucleotidases were and like other protozoan parasites is unable to synthe- probably present. The authors concluded from further size purines and therefore depends on purine salvage experiments that ATP activates non-sclective cation chan- from the host environment; hypoxanthine transport oc- nels in medial noxious cells of the leech with an order of curs via a high affinity, energy-dependent transporter potency ATP ADP AMP They claimed that the results with a substrate specificity that is markedly different from suggest that these cells express purinoceptors of the P2 any known mammalian nucleobase transporter [de type, although suramin was not an effective antagonist of Koning and Jarvis, 19951. this receptor. Salivary cells of the leech Haernenteriu ghiZianii cxhibit a selective response to ATP producing Platyhelminths inhibition of voltage-dependent Ca2+influx [Werner et ATP diphosphohydrolase has been located on the al., 19961; ATE but not adenosine, modulates action 130- external surface of the tegument of the parasitic liver tential firing, thought to be via a niammalian-like P2-pu- fluke, Schistosoma rnansoni; it is suggested that this en- rinoceptor [Wuttke and Berry, 19931. Alater study showed zyme could regulate the concentration of purine nucle- that the PS-purinoceptor involved is suramin-insensitive otides around the parasites and hence enable them to and that activation by ATP inhibits Ca2+influx throi~gh escape the host haemostasis by preventing ADP-induced voltage-gated Ca2+channels [Wuttke et al., 19963. platelet aggregation [Vasconcelos et al., 19931. Molluscs Coelenterates Molluscs do not show segmentation, the body con- Encompassing the jellyfish, sea anenomes, and cor- sists of a head-foot and visceral mass extended into folds als, these mainly marine organisms are radially symmetri- which often secrete a shell. The nervons system consists cal with a two layered body wall enclosing a single cavity of ganglia connected by commisures. This group includes with a single aperture, the mouth. snails, bivalves, and octopuses. The pedal disc of the sea anenome Actinia eqina Adenosine has been shown to have a modulatory has been shown to posse purinoceptor that is respon- effect on an excitatory ACh response on an identified sive to ATE: ADE and adenosine, all of which cause con- neuron (F,) of the suboesophageal ganglion of the snail tractions, but is insensitive to AMP [Hoyle et al., 19891 Helix aspersa; it was proposed that an Al-receptor medi- (Fig. 6). A role of ATP in the maturation of nematocysts ated inhibition, while an A2-receptor mediated enhance- from sea anenomes has been suggested [Greenwood et ment of the response to ACh [Cox and Walker, 19871. ATP al., 19891. A purine, caissarone, extracted from the sea and a,P-meATP also enhance the response, suggesting anemone, Bunodosomz caissarurn,has been shown to be that a P2X-purinoceptor is also present. Nanomolar con- an adenosine receptor antagonist [de Freitas and Sawaya, centrations of extracellular ATP and its stable analog 1990; Cooper et a]., 199.51. ATP causes ciliary reversal in AMP-PNP were also shown to activate calcium channels the comb plates of ctenophores, probably by increasing in these neurons [Yatani et al., 19821 (Fig. 7). Single neu- intracellular Ca2+ions [Nakamura and Tamm, 1985; rons in ganglia of the marine mollusc ApZysia californica Tamm and Tamm, 19891. contain highly variable levels of ATP and lower levels of related purines, including ADE AME adenosine, and Annelida inosine [Stein and Weinreieh, 1984; McCarnan, 19861, in This phylum comprises the segmented worms, in- keeping with the possibility that some are involved in cluding the polychaetes, oligochaetes, and hirudines. The purinergic transmission. worms possess both circular and longitudinal body Adenosine modulates monoamine release hom neu- muscles. The nervous system consists of dorsal cerebral rons in the pedal ganglion of the marine hivalve Mytihs 21 4 BURNSTOCK

AT P Ado 135 7 9mM mrrrr r r

4 min A A A 1mM 2mM 3mM

% Maxinurn contractton 100

60 A = ATP

40 a= ADP A = Adenosine 20

1 I 35 3a 2.5 2.0 1.5 iog (Punel

Fig. 6. Actions of adenylyl compounds on isolated circular muscle of Symbols show mean percentage maximum contraction due to the ade- the pedal disc of Actinia equina. Upper panels: Examples of contractile nyl compound ? S.E.M. (unless occluded by symbol). Solid lines are the responses to ATP and an example of a cumulative concentration-response curves fitted following probit transformation and horizontal averaging. relationship for adenosine (Ado). lower panel: Conccntration-response For clarity the curve for adenosine has not been drawn, as it overlies the curves for ATP ( A,n = 121, ADP (0,n = 101, and adenosine (A,n = 7). curve for ADP. Reproduced from Hoyle et al., 1989. edulis; analogucs of adenosine are also capable of inhib- by ATP and electron microscopy revealed different types iting transmitter release, the receptor, being highly spe- of nerve profiles, some containing large opaque vesicles cific for NECA, exhibits the characteristics of the and staining for Mg-ATPase and 5 '-nucleotidase which mammalian A,-receptor [Barraco and Stefano, 19951. resembled NANC purinergic nerves observed in mam- Adenosine deaminase has been identified in M&LS malian gut [Sathananthan and Burnstock, 19761. Adenos- edulis [Aikawa and Aikawa, 19841 as well as in the ad- ine has also been shown to cause systemic arrest of diictor muscle and midgut of the scallop, Putinopecten pulsations in the isolated heart auricle of the oyster yassoeizsis [Sato and Aikawa, 1991; Yoshida and Aikawa, Cmssostreu nipponu, but only in alkaline conditions, he- 19931, which is consistent with a role for adenosine as an cause the specific enzyme involved has a low optimum extracelliilar modulator. pH as a protective device [Aikawa and Ishida, 1966; Studies of the systemic heart of the cephalopod Aikawa et al., 19671. The hearts of Rzisycon contrariuin Octopus vulgaris have shown that adenosine has an op- and Melongerta corona responded in a complex way to posite effect to that known for the mammalian heart, in purine compounds, ATP causing 110th positive and nega- that adenosine and AMP produced positive chronotro- tive inotropy [ Hoyle and Greenherg, 19881. The same is pic and inotropic effects [Agnisola et al., 19871. The heart tnie for the hearts of the snail Helix uspersn and the slug of the Venus clam, Kutelysiu rhyctiphoru, is stimulated Arion nter where the responses to ATE ADT: AME: and ad- ONTOCENY AND PHYLOGENY OF PURINOCEPTORS 215

TABLE 1. Quantitative Effects of Extracellular Nucleotides on Leech Neurons and Neuropil Clial Cells'

ATP ADP AMP Adenosine ATP- y- S

Annulus erector cell 2.8 ? 1.6 (20) 6.3 (2) 2.5 (2) 1.5 2 1.3 (3) -4.2 t 2.3 (3) Anterior pagoda cell 1.7 ? 2.7 (6) 2.0 ? 2.9 (6) 0.9 t 2.0 (5) 2.0 ? 2.0 (3) 3.5 ? 1.8 (10) -2.8 ? 1.3 (5) Retzuis cell 2.1 ? 0.9 (7) 1.3 ? 0.8 (6) 1.3 ? 0.8 (6) 1.3 t 0.5 (4) 10.4 t 2.2 (10) Medial noxious cell 4.5 ? 5.9 (35) 4.0 ? 1.7 (7) 2.7 ? 2.4 (7) 1.3 ? 1 .0 (8) 6.4 * 2.0 (32) Lateral noxious cell 6.9 2 3.5 (8) 9.6 ? 0.9 (7) 5.2 t 1.8 (6) 5.4 2 1.5 (8) Not tested Medial pressure cell 3.2 ? 2.2 (8) 2.4 t 1.0 (7) 0.4 ? 0.8 (7) Not tested 3.7 ? 2.3 (5) Lateral pressure cell 1.2 ? 2.0 (3) 1.8 t 1.8 (3) 0.7 2 1.2 (3) 1.5 (2) 1.3 ? 0.5 (5) Touch cell 6.4 ? 4.6 (4) 4.5 2 2.8 (5) 2.9 ? 1.7 (5) 4.0 ? 3.0 (4) 3.0 ? 0.9 (3) Neuropil glioal cell 0 (6) 0 (6) 0 (6) 0 (6) 0 (3)

'All agonists were applied at a concentration of 100 pM except ATP-y-S (5 pM). The numbers give the mean depolarisation in mV 2 the standard deviation. The number of experiments is given in parenthesis, Negative values indicate hyperpolarisations. Reproduced from Bakus et al., 1994. enosine caused either cardioexcitation or cardioinhibition aparently via a specific ATP/ADP receptor [Deyrup-Olsen in any given preparation [Knight et al., 1992~1. et al., 19921. In general, nerves in the heart and gut of the Probiscis smooth muscles of Buccinurn undaturn pulmonate gastropod molluscs show a high affinity for respond to GTP and GTPF (but not to ATP or adenos- quinacrine [Cardot, 1981; Knight et al., 19!Eb] suggest- ine) in the 10-7-10-3M range with a moderately fast twitch ing that they contain high levels of granule-bound ATl? activity which was unaccompanied by action potentials [Nelson and Huddart, 19941. Both the oesophagus and Arthropods the rectum of the snail, Helix aspersa, produced contrac- The phylum arthropoda includes crustaceans, cen- tions to ATE ADE and AME but the synthetic analogs 2- tipedes, millipedes, insects, and arachnids. They are chloroadenosine, a,P-meATP and 2meSATP were characterized by their bilateral symmetry and typically inactive [Knight et a]., 1992al. each segment has a pair of jointed appendages at least The body wall of the pulmonate slug, Ariolimux one pair being modified as jaws, although the number of columbianus, secretes mucous packaged in granules; segments included in the head is variable. There is a newly secreted granules rupture in the presence of ATE strong and well-developed exoskeleton. The CNS consists of cerebral ganglia and a ventral nerve cord made up of separate paired ganglia connected by commisures. There is a contractile heart lying in a haeniocoelic peri- cardial cavity.

Crustacea There is considerable information about the effects of ATP and adenosine in crustaceans. The olfactory organ of the spiny lobsters Panulirus argus and Panulirus interruptus have different populations of purinergic chemoreceptors that are excited by AME ADI: or ATP [see Carr et al., 1986, 1987; Zimmer-Faust et a]., 1988; Trapido-Rosenthal et al., 19891 (Fig. 8). These receptors reside on chemosensitive neurons that are contained within aesthetasc sensilla on the lateral filaments of the antennules. 5 '-AMP odorent receptor sites have recently been localized ultrastructurally, utilizing 5 'AMP-biotin, along the entire dendritic region, including the transi- log concentration (M) tional zone between inner and outer dendritic segments, the region which also contains 5 ' -ectonuclotidase/phos- Fig. 7. Activation of Ca2+ channels on Snail neurones: Dose-response phatase [Blaustein et al., 19931. curves for the effects of extracellular ATP (0)and AMP-PNP (0)on Ira The potency order for some sensilla indicates a P1- (elicited by a 70 ms long pulse to t20 mV from a holding potential of -50 mV). Each point represents the mean of six measurements for ATP and purinoceptor [Derby et al., 1984, 1987; Carr et al., 1986, seven for AMP-PNP obtained from different neurones (curves were drawn 19871. In addition, there are chemoreceptors stimulated by eye). Reproduced from Yatani et al., 1982. by ATP exhibiting properties similar to P2-purinocep- 21 6 BURNSTOCK

isms, such as mussels and oysters, which contain high conccntrations of nucleotides and arc released when the animal dies [Carr and Derhy, 19861. ATP acts as an effective signal molecule in seawater, since mechanisms exist in seawater that minimise the presence of background AMP ( IpM) ATP levels that might represent a false indication of thc prescncc of food [Zimnier-Faust et al., 19881. These nicchanisms include ctepliosphoiylating enzymes present - lbf 4 5ec on the outer surfaces of many planktonic organisms which quickly degrade nucleotides released into the sea [Amnierman and Azani, 19851 in addition to nucleotidascs in tissues that rapidly dephosphorylate ATP after death [Zinimcr-Faust, 19873. Hence the presence of appreciable concentrations of ATP in seawater may provide a reliable indicator that an injured or freshly killed prey is nearby. While ATP is a potent attractant, AMP has an inhibitory effect on some lobsters [Gleeson et al., 1989; Zimmer-Falist, 19931 and may therefore act to direct the predator towards only fresh prey. For those predators in Id1 0 2 5ec which AMP acts as the attractant [Carr and Thompson, 1983; Derby et al., 1984; Carr et al., 19871, the rapid breakdown ofA’TP to AMP may account for this. AMP is found Fig. 8. Comparisons of response characteristics of AMP-sensitive and to be the most potent chenioattractant of Octopus vul- ATP-sensitive cells in the antennule of the spiny lobster. a: Response of AMP-best cells to the indicated compounds. b: Series of action poten- garis, initiating a locomotor response. The arms are be- tials produced by an AMP-best cell to the indicated concentrations of lieved to carry the sensory organs, chemoreceptors having AMP. c: Response of ATP-best cells to the indicated compounds. d: Se- been morphologically identified in the suckers [Chase ries of action potentials produced by an ATP-best cell to the indicated and Wells, 19861 which would direct the arms towards concentrations of ATP. Note the differences in time scale in (b) and (d). the nieal. Modulatory actions of AMP and adenosine were Reproduced from Trapido-Rosenthal et al., 1989. recorded in brain cells of the spiny lobster [Derby et al.. 1987; Derby, 19871; AMP was the most potent ofthe pii- tors [Carr et al., 19861. Since these receptors are more rincs cxamined and its effect was antagonizcd hy theo- sensitive to the slowly degradable analogues of ATE: a,P- phyllinc. Olfactory purinoceptors have also been nicATP and P,y-nicATP [Carr ct al., 19871, they appear identified in the shrimp Pulaemonetes pugio [Carr and to he comparable to the P2X family of purinoceptors. Thompson, 1983; Carr and Derby, 19861 and blue crab Siniilarities 1)etwec:n the PI- and P2-purinoceptors of Callinectes supidus [Buch and Rechnitz, 19891. these crustaceans and mammalian purinoceptor subtypes In lobsters and other decapod crustaceans, the sites arc cxtcndcd furthcr, in that thc chcmoscnsory scnsilla of olfaction and gustation are anatomically distinct, the inactivate excitatory nucleotides by a two-step proccss. former in the antennules, the latter on the walking legs, Ectonucleotidases dephosphorylate adenine nucleotidcs maxillipecls and mouthparts; the sensilla on the walking to yield a nucleoside which is internalised by an uptake legs of the spiny lobster, Punulirus argus, have also been system [Trapido-Rosenthal et al., 1987, 19901, which is shown to possess ATP- and AMP-sensitive cells as well similar to mammalian systems [Bnrnstock, 19751. as enzymes that dephosphorylate purine nucleotides Activation of olfactory (smell) and gustatory (taste) [Glccson et al., 19891. P%purinoceptors in 1ol)sters is thought to indnce a feed- Extracellular ATP has been shown to modulate cal- ing liehavioural response [Fine-Levy et al., 1987; Zirnmer- cium uptake and transmitter release from neuromuscu- Faust ct al., 1988; Daniel and Derby, 1989; Gleeson et lar junctions in the walking leg of the crayfish, al., 1989; Zimmer-Faust, 19931. ATP is an ideal stimulus Procumburus clurkii [Lindgren and Smith, 19871, remi- for such animals that fcccl on woundcd or recently killed niscent of purinergic modulation of transmitter release animals, since ATP occurs at high concentrations in fresh at the skeletal neuromuscular junction of vertebrates animal flesh 1)ut decays rapidly as cells die [Sikorski ct [Ribeiro and Walker, 1975; Redman and Siliiisky, 19931. a]., 19901. Since predators, such as lobsters, often inhabit The inhibitory effects of ATP on the heart of the crevices and only emerge to feed at night, foraging is di- spiny spider crab, Maiu, wcx-c reported iiiariy years ago rectcd principally lly chemical stimuli, rather than visual [Welsh, 19391. ATP potentiates the effects of electrical or mechanical stimuli. ATP is detected in prey organ- field stimulation of neiirons in the terminal intestine of ONTOGENY AND PHYLOGENY OF PURINOCEPTORS 21 7 the lobster Panulirus argus via a P2-like purinoceptor purinoceptor [Galun et d.,1963,1985; Galun and Margalit, [Hoyle and Greenberg, 19881. 1969; Mitchell, 1976; Galun and Zacharia, 19843. A similar Arteinia is a crustacean whose embryos become ATP-selective receptor mediates the phagostimulatory encapsulated at the gastrula stage. The cysts are viable response of Glossina tachinoides [Galun, 19881 and for years in a dry environment. When placed in a suit- Rhodnius prolixus larvae, suggesting that this response able saline medium, the eggs resume their development is not limited to the adult form [Smith, 1979; Friend and and differentiate into free swimming larvae at about 24 Smith, 19821. Further investigations have revealed that h. During this time, Artemia uses the maternal stored the receptor can be subclassified; a,P-meATP and P,y- diguanosine tetraphosphate (Gp,G) as a source of gua- meATP are less potent than ATP as phagostimiilants in nine and adenine nucleotides during development from G. palpulis palpalis suggesting that the receptor may be encysted gastrulae to free swimming larvae [Finamore tentatively classified as a PZY-purinoceptor [Galun and and Clegg, 1969; Sillero and Sillero, 1987; Warner, 19921. Kabayo, 19881. A similar order of potency is found for Artemia cysts contain the appropriate enzymatic machin- Rhodnius prolixus [Friend and Smith, 198.21. However, ery for the conversion of Gp4G into AMP and GMP since 2meSATP, which is a more selective P2Y- [Prescott et al., 19891. However, Artemia is apparently purinoceptor agonist, has not been investigated, the clas- unable to synthesize purines de novo [Clegg et al, 19671 sification of this receptor is still uncertain. and the larvae depend on a balanced dietary source of A P2-purinoceptor has also been identified that purines (nucleotides, nucleosides, or bases) for growth inititates feeding of the culicine mosquitoes Culex pipiens and survival to adulthood [Hernandarena, 1985, 1990; and Culiseta inornatu. The potency order was found to Sillero et al., 19931. be ADP >ATP=AMP>P,y-meATP for C. pipiens and ADP>ATP>P,y-meATP> >AMP for C. inornata [Galun Insects et al., 19881. ADP is also found to be the most potent ATP released from erythrocytes stimulates the gorg- phagostimulant of the horsefly Tabanus nigrovittatus ing response in a variety of blood-feeding insects such as [Friend and Stoffolano, 1983, 19841. ADP-selective re- the mosquitoes Aedes uegypti and caspius, Culex pipiens ceptors, termed PzT-purinoceptors,have hen identified univittatus and quinyuefasciatus and Culiseta inornatu, in mammals [Gordon, 19861. However, the ADP-selec- the blackfly, Sirnulium venusturn [Sutcliffe and McIver, tive receptor of the haematophagous insects differs from 19791, the horse fly, Tabanus nigrovittutus [Friend and the mammalian receptor where ATP acts as a competi- Stoffalano, 19841, the stable fly, Stornoxys calcitrans, tive antagonist [Macfarlane and Mills, 19751. ATP behaves the tsetse fly, Glossina austeni morsitans, tachinoides, as an agonist at the insect receptor. The potency orders and palpalis, the bug, Rhodnius prolixus and the of the purine nucleotides vary considerably between dif- haematophagous ticks, Zxodesdarnrnini and Boophilus ferent groups of haematophagous insects; however, inicroplus [Hosoi, 1959; Galun et al., 1963,1985,1988; closely related species usually show a similar structure- Galun and Margalit, 1969; Friend and Smith, 1975, activity relationship. It has been suggested that a pre- 1977; Smith, 1979; Ribeiro et al., 1985; Willadsen et al., existing pool of nucleotide-binding proteins, present in 1987; Ellgaard et al., 1987; Ascoli-Christensen et al., 1991; all living cells, served as a source of the receptor pro- Liscia et al., 1993; Moskalyk and Friend, 19941. teins for the gustatory receptors involved in blood detec- Electrophysiological methods have been used to tion and that the selection of any such nucleotide bindng demonstrate that the apical sensilla of the labrum ofCulex protein was random [Galun, 19871, perhaps accounting pipiens house the ATP receptors involved in blood feed- for the variety of receptor profiles found among the ing [Liscia et al., 19931. Novobiocin, which blocks ATP haematophagous insects. access to its binding site on ATPase, inhibits the gorging The potency order of various adenine nucleotides response [Galun et al., 19851. The EDjo ofATP for Glos- suggests the receptor involved is of the P2-subtype [see sina tuchinoides females is 13 nM, while for males it is Galun, 1987, 1988; Galun et al., 19881 (Table 2). In the 140 nM; this level of sensitivity for detecting ATP is the tsetse fly Glossina palpalis, P2-purinoceptor stimulating highest recorded for an insect [Galun and Kabayo, 19881. gorging has been identified as being of the P2Y-subtype Other chemosensory P2-purinoceptors have been [Galun and Kabayo, 19881; in contrast, in the stable fly identified that are involved in the recognition of a blood the ATP-mediated response is antagonised by ANAPP3, meal in haematophagous insects. These represent a het- suggesting a receptor that resembles the P2X-purinocep- erogeneous group. Many hlood-feeding insects recognize tor subtype [Ascoli-Christensen et al., 19'311. The P2- ATP and related compounds as phagostimulants. In mos- purinoceptor of G. morsitans morsitans was not classified quitoes and tsetse flies, ATP is found to be more potent further, although it was noted that the phosphate chain than ADP at stimulating feeding while AMP is a very was of importance [Mitchell, 19761. Both AMP and ATP poor phagostimulant, indicating an ATP-selective P2- were also found to be potent chemoattractant s, with equal 21 8 BURNSTOCK

TABLE 2. Gorging Response of the Tsetse Fly, Glvssia fachinvides, to and platelets have been implicated as the gorging stimu- Adenine Nucleotides* lus of Aedes tzegypti [Galun and Rice, 19711. Taste cbemosensilla sensitive to nucleotides have Compound No. flies EDSO(1M) ED85 been identified in some non-haematophagous insects, Females for example, in the omnivorous common blowfly, ATP 240 0.01 3 (0.007-0.024) 0.20 (0.10-0.42) Phurmiu reginu [Daley and Van de Berg, 1976; Liscia, ADP 210 0.063 (0.034-0.15) 1.30 (0.50-3.8) AMP 135 69.5 (36.4-133) 1060 (308-3640) 1985; Liscia et al., 19871. In this species, ATP does None 7 05 27% fed not have a direct stimulatory action, hut rather inodu- Males lates the responses of the labilla sensilla; it reduces ATP 180 0.14(0.12-0.19) 0.56 (0.31-1.02) the responses to NaCl and fructose, but enhances re- None 30 7% fed sponses to sucrose and glucose [Liscia, 19851. Cyclic *Figures in parenthesis are 95% confidence limits. Reproduced from AMP inhibits neuronal firing ofthe labellar sugar sen- Calun, 1988. sitive receptor of the blowfly when applied in con- junction with the stimulant sucrose [Daley and Van de Berg, 19761. ATP has also been reported to be a potency, for the larvae of Culex yuinyuefusciutus, although feeding stimulant in a flea, Xennpsyllu chenpis [Galun, unlike the adult stage, the phosphate chain is not as im- 19661 and a tick [Galun and Kindler, 19681. portant, since adenosine was found to be a moderate Adenosine stimulates feeding in the African army- chemoattractant [Ellgaard et al., 19871. It is fascinating worm Spodopteru exemptu; this larva of an owlmoth ex- that apyrase (ATP diphosphohydrolase), a general desig- clusively feeds on grasses [Ma, 19771. Other purines and nation for enzymes that hydrolyze ATP and ADe has been pyrimidines have no such phagostimulatory activity in- reported to have exceptionally high activity in the sali- dicating an adenosine-selective receptor. The function vary glands or saliva of blood sucking insects, includ- of the styloconic sensilla in determining the chemosen- ing the bug Rhodnius prolixus [Ribeiro and Garcia, sitivity to adenosine in this animal was examined by Ma, 1980; Smith et al., 1980; Sarkis et al., 19861, tsetse fly who found that addition of a ribose group to thc N6 posi- [Mant and Parker, 19811, mosquito [Ribeiro et al., tion of the adenine molecule greatly enhances its effec- 19841, and sandfly [Ribeiro et a]., 19861. In all cases, tiveness as a stimulus. D-ribose itself failed to excite any since ADP induces platelet aggregation, hreakdown receptor cell in the lateral sensilla, but did stimulate some of ADP hy apyrase leads to enhanced haemorrhage neurons in the medial sensilla. and more effective lilood sucking [see Ribeiro, 19951. Adenosine inhibits adenylate cyclase in the pupa1 In ticks, where each engorgement generally extends fat body of the silkworm, Bornbyx rnori with characteris- over severaI days, the saliva has antiinflammatory and tics comparable to those known for neuroinuscular ad- immunosuppressive properties as well as platelet anti- enosine receptors, Al subtype [Morishima, 19801. aggregative apyrase and Mg‘*+/ATPase[Ribeiro et a]., 198s; Willadsen eta]., 19871. Echinodermata The involvement of purines in the recognition of a This pliylum includes the starfishes, sea urchins, blood meal in haematophagous insects is interesting. Both brittle stars, feather stars, and sea cucumbers. The adults platelets and red blood cells (RBC) release ATP and ADP have acquired a large measure of radial symmetry (usu- as a result of wounding [Mills and Thomas, 1969; Born, ally five-rayed) and often an ectoskeleton develops. There 19771; which source offers the stimuliis to feed depends is a water vascular system which is linked to the tube on the insect in question, some species are more sensi- feet assisting in locomotion as well as a ‘perihaemal’ blood tive to ATE while others are more sensitive to ADE For vascular system which is less extensive. The nervous sys- instance, ATP released from RBC preferentially induces tem consists of a nerve ring around the oral part of the Rhodnius prolixus to gorge, since plasma, which contains gut with projections along the radii. Many echinoderms little ATP [Bishop et al., 19591, is considerably less effec- have a deeper-lying motor nerve component. tive than a suspension of washed erythrocytes [Smith, There are several reports of the ef’fects of purine 19791. The potency ofthe erythrocyte suspension is as- compounds on echinoderms. In a review of several ma- sociated with RBC contents rather than the erythrocyte rine species, Hoyle and Greenberg [1988] found that ad- membrane, since RBC ghosts are ineffective as gorging enosine, AMP, ADP, and ATP all relaxed the gastric stimulants [Smith, 19791. It is suggested that the release ligament of the starfish, Asteriusforbesi with ATP being of ATP from RBC close to the mouth sense organs act as the most potent of the purines examined. the feeding stimulant. Platelets also contain quantities of In a later study, Knight et al. [1990] showed that, in ATE both ATP and ADP are released into the plasma by the precontracted gastric ligament in the starfish,Asterias appropriate triggers such as wounding [Holmsen, 19721 rubens, the relaxation to ATP was antagonized by glib- ONTOGENY AND PHYLOGENY OF PURINOCEPTORS 21 9 enclaniide; in contrast, relaxation to adenosine, which was the cyclostomes comprise one class, and Gnathostomata, equipotent to ATP in this species, was not blocked by encompassing all the more familiar vertebrates, includ- glibenclamide, supporting the view that separate recep- ing elasmobranchs, teleosts, amphibians, reptiles, birds, tors for adenosine and ATE comparable to PI- and and mammals. P2- purinoceptors of vertebrates, exist in the echinoderms. However, the antagonists for P1- and P2-pu- Cyclostome Fish rinoceptors, effective in most mammalian preparations, These are primitive cartilaginous fish and include 8-phenyltheophylline (8-PT; for P1-purinoceptors), Re- the lampreys and hagfish. In the hagfish Myxine gluitinosa active Blue 2 (for P2-purinoceptors) and desensitization adenosine has been observed to dilate the isolated bra- of the P2-purinoceptors with a,P-meATP were ineffec- chial vasculature, although it had no effect on the heart tive in the starfish preparations [Hoyle and Greenberg, [Axelsson et al., 19901. Specific binding of the P1 (A,) 1988; Knight et al., 19901. It is not clear why glibenclamide, adenosine receptor ligand [3H]cyclohexyladenosine which is a potent inhibitor of ATP regulated-K+ channels (CHA) to membrane fractions from the brain of the hag- in mammalian preparations, is effective in antagonking re- fish, Eptatretus deani, was demonstrated as well as in elas- sponses of the starfish gastric ligament to ATE: but it does mobranch and teleost fish, but not from the brains of suggest that glibenclamide may be a useful tool for ex- arthropods or molluscs [Siebenaller and Murray, 19861. amining purinoceptor subtypes in invertebrates. The circular and longitudinal muscles from the polian vesicle of Elasmobranch Fish the sea cucumber, Thyone briareus relaxed to ATE: but There are various reports of the effect of purine not to adenosine, AMP and ADE: suggesting an ATP-spe- compounds within this group of cartilaginous fish, includ- cific receptor [Hoyle and Greenberg, 19881;however, the ing reactivity in both the gastrointestinal and cardiovas- rectum of the sea urchin, Lytechinus variegatus, con- cular systems. The spontaneous activity in various tracted equipotently to all four purine compounds which preparations of elasmobranch gut is inhibited by ATE: may indicate a non-selective receptor or the presence of such as the stomach and spiral intestine of the ray Raja both P1 and P2 receptors which can only be confirmed clavata and the dogfish, Scyliorhinus canicula, and rec- by the use of selective antagonists. ATP produces tonic tum of Raja [Young, 1983, 19881. ATP was reported to contractions of the spine muscle of the sea urchin, cause contraction or relaxation of the stomach of the dog- Anthocidaris crassispina [ Shingyoji and Yamaguchi, 19951. fish [Young, 19801, contraction of the stomach of the ray Other diverse effects of purine compounds have also [Young, 19831 and relaxation of the rectum of the skate been identified in echinoderms. For instance, adenosine [Young, 19881. Both Al- and A,-adenosine P1.-purinocep- inhibits the growth of fertilized eggs of the starfish, tor subtypes have been identified in the rectal gland of Asterina pectinqera, at the early blastula stage, specifi- the shark, Syualus acanthias, which modulate hormone cally at the 256-cell stage; adenosine causes more than a stimulated chloride transport [Kelley et al., 1990, 1991; 95% reduction in the rate ofprotein, DNA and RNA syn- Forrest and Kelley, 1995; Forrest, 19961. thesis [Tsuchimori et al., 19881. Effects are not limited to An inhibitory PI-purinoceptor has becn identified the blastula stage; muscular activity of sea urchin in the atria of the dogfish S. canicula [Meghji and Burn- Psamrnechinus miliaris larva is stimulated by adenosine stock, 1984al and the possibility of purinergic modula- [Gustafson, 19911. tion of vagal control of the heart of S. stellaris has been ATP and its stable analog AMP-PNP modulate investigated [Taylor et al., 19931; in another species of flagellar motility of the sea urchin Lytechinus pictus, dogfish, Squalus acanthias, both Al- and A2-subtypes of [Brokaw, 1975; Penningroth and Witman, 1978; Omoto receptor have been characterized in the aorta [Evans, and Brokaw, 19893. This effect has been interpreted 19921. In the coronary artery of the skate Raja nasuta, largely in terms of the intracellular actions of ATE the adenosine causes vasoconstriction, while ADP and ATP possibility that extracellular P2-purinoceptors are in- cause vasoconstriction at lower concentrations, but va- volved needs to be considered. sodilatation at higher concentrations [Farrell and Davie, 1991bI; in the dogfish 10 FM ATP produced contraction lower Vertebrates followed by relaxation [Farrell and Johanson, 19951. In contrast, in the coronary artery of the mako shark, Isurus The vertebrates, which are a sub-phylum of' oxyrinchus, adenosine is a dilator, as in the dogfish, and Chordata, are characterized by the presence of a noto- ADP a vasoconstrictor; theophylline inhibited both the chord at some time during their life-history and a high adenosine-mediated relaxation and the ADP-mediated degree of cephalisation so that a proper head region is contraction [Farrell and Davie, 1991aI. recognisable, with a definite brain enclosed by a cranium. The electric organ of electric elasmobranch fish, The group contains two superclasses: Agnatha, of which which is phylogenetically derived from neiiromuscular 220 BURNSTOCK junctions, consists of motor nerves and electrocyte cells iius toxin [Rabasseda et al., 19871,and omega-conotoxin forming electroplaques that are derived from myolilasts. differentially blocks ACh and ATP release [Farias et al., Synchronous discharge of the electrocytes by motor nerve 19921.A high affinity adenosine uptake system has been stimulation produces a total discharge of about 40 V; It demonstrated in the synaptosomes for reconstitution of has been shown that ACh and ATP are co-stored (in a stored ATP [h4eunier and Morel, 1978;Ziininerniann et ratio of about 5:l)and co-released during synaptic activ- al., 1979;Tomas et al., 19821. Isolated synapatic vesicles ity of the electric organ of the electric eel, Electrophorus from Torpedo electric organ contain about 200,000 mol- and the electric ray, Torpedo [Meunier et al., 1975; ecules of ACh and about 24,000 molecules of ATP; small Zimmermann & Denston, 1976; Dowdall et al., 1974, amounts of ADP are also present (10% of ATP content) 1976; Tashiro arid Stadler, 1978; Stadler and Fuldner, and traces of AMP [Zimmcrmann, 19821.The diadenos- 1981).Release of ATP from syriaptosornes isolated from ine polyphosphates, Ap,A and Ap5A are both present in the electric organ ofTorpedo by either depolarisation with synaptic vesicles of Torpedo murmoruta and binding of KCI or after the action of venom extracted from the an- Ap,A to P2-purinoceptors has been demonstrated in Tor- nelid Glyceru, exhibited closely similar kinetics to that pedo synaptosomes [Pintor et al., 19941.Vesicles from the of ACh release [Morel and Meunier, 19811 (Fig. 9). Both closely related Narcine electric organ contain consider- ACh and ATP release are inhibited by the removal of able amounts of GTP (17% of ATP content). One func- extracellular Ca2+or by the addition of the calmodulin tion for the ATP is that it increases receptor sensitivity to antagonist, trifluoperazine, suggesting that ACh and ATP ACh [Akasu et al., 1981; Schrattenholz et al., 19941,i.e.. are both released by cxocytosis from synaptic vesicles it acts as a postjunctional modulator. A further role is [Schweitzer, 1987;see also Unsworth and Johnson, 1990, that adenosine resulting from hydrolysis of ATP by and Solsona et al., 19911, although it is interesting that ectoerizynies acts as a prejunctional modulator of ACh ATP release (in contrast to ACh) is not blocked by teta- release [Ginsborg and Hirst, 1972; Israel et al., 1977: Keller and Zimmermann, 1983; Grondal and Zimmer- mann, 1986;Grondal et al., 1988; Sarkis et al., 19911.The ability of bound ectoenzymes, obtained from Torpedo electric organ synaptosomes to dephosphorylate ATP to adenosine supported this hypothesis [Grondal and Zimmermann, 19861.This was later further substantiated as a result of chemiluminescent investigations [Solsona et al., 19901 and studies showing that adenosine can inhibit ACh release [Israel et al., 19801.A cDNA encoding 5 '-nucleotidase was identified by screening a cDNA li- braiy from the electric lobe of the electric ray, Discopygv ornmatu using a cDNA probe for the rat liver enzynie [Volknandt et al., 19911; the possiblc phylogcnetic ori- gins of vertebrate 5 '-nucleotidase from multi-functional nucleotide hydrolases is described in this paper.

Teleost Fish ATP and adenosine both produced relaxation of the intestine of the Atlantic cod, Gadus rnorhua [Jensen and Holmgren, 19851, and the circular muscle of the stom- Fig. 9. Torpedo electric organ: ACh and ATP release from synaptosomes ach of the rainbow trout, Salrno gairdneri [Holmgren, triggered by venom extracted from the annelid Clycera convoluta. Syn- 19831.However, ATP contracts both the longitudinal and aptosomal ACh was labelled using [I -'4Cl-acetate. Concentrated synap- circular muscle layers of the intestinal bulb of the carp, tosomes deriving from 1.8 g electric organ were perfused with the Cyprinus curpio [Kitazawa et al., 19901, the intestine of physiological medium for 15 min. When a constant background radioactivity was obtained, the perfusion was switched to KCI solutions (where the angler fish Lophius [Young, 19831 and the intestine of KCI replaces equivalent amounts of NaCI). Venom was used at a final the goldfish (Carussius uurutus) [Burnstock et al., 19721. concentration of 0.5 glandsiml physiological medium. The perfusate was Adenosine relaxed the stoinach and intestine of the stick- collected by 200 pl aliquots and the efflux of radioactivity and of ATP leback, Gasterosteus aculeatus, and this response was determined in each aliquot. The specific radioactivity of synaptosomal antagonized by 8-PT, indicating the presence of a P1- ACh was 700 cpminmol and the ACh/ATP ratio in the synaptosomes was 6.9. Sixty-five percent of injected synaptosomes was retained in the per- purinoceptor; ATP and its analogs, 2meSATE and a,P- fusion chamber at the end of the experiment. Reproduced from Morel meATP caused contractions of the stomach and intestine, and Meunier, 1981. indicating a P2-purinoceptor [Knight and Burnstock, ONTOGENY AND PHYLOGENY OF PURINOCEPTORS 22 1 19931. ATP has been found to closely mimic the NANC (Miyashita et al., 1984), of both melanophores and responses to vagal stimulation of the pyloric caeci and iridophores in the blue damselfish, Chrysiptera cyanea duodenum of Lophius, even at very low concentrations, [Kasukawa et al., 1985, 1986; Oshima et a]., 1986a1 and producing an inhibition followed by a rebound contrac- ofleucophores in the medaka [Oshima et al., 1986111. In tion [Young, 19801. The possibility that there is a NANC more recent studies of denervated melanophores in the inhibitory innervation of the gut of the brown trout Salmo medaka, Orzjnias latipes, the potency series for melano- trutta was hinted at, although the concept of NANC in- phore dispersion was: NECA>adenosine>ATP >2- nervation was unknown at the time of the investigation chloroadenosine (2-CADO)> R-PIA>CHA>cAMP; this [Burnstock, 1958, 19591. The ileum and rectum of the effect was antagonized by 8-PT and by adenosine deami- flounder, Pleuronectes, both possess excitatory PSX-pu- nase and the action of adenosine was mimicked by for- rinoceptors and inhibitory P1-purinoceptors [Grove and skolin, a potent activator of adenylate cyclase [Namoto, Campbell, 1979; Lennard and Huddart, 1989aI. 1987, 19921. It was concluded that the P1-purinoceptor Examples of the presence of various types of pu- involved was of the A2 subtype. Evidence that ATP is rinoceptors within the cardiovascular system include a liberated as a cotransmitter together with noradrenaline P1-purinoceptor in the gill vasculature of the rainbow from melanosome aggregating sympathetic nerves in the trout, Salrno gairdneri, and of the tropical cichlid, tilapian fish, Surotherodon niloticus, has been presented Oreochromas niloticus, that mediates vasoconstriction [Kumazawa et al., 1984; Kumazawa and Fujii, 1984,19861. [Colin and Lerajr, 1979, 1981; Colin et al., 1979; Okafor It seems likely that ATP released from sympathetic nerves and Oduleye, 19861. A P2-purinoceptor is also likely to is broken down by ectoenzymes to adenosine which then be present in the gill vessels since the contraction po- acts on P1-purinoceptors both on chromatophore mem- tency order of purine compounds in the rainbow trout branes leading to dispersion of pigment, and also on was ATP=ADP>AMP=adenosine [Colin and Leray, prejunctional sites leading to modulation of sympathetic 19791, while ATP produced vasodilatation in cichlid transmitter release [Oshima, 19891. In a more recent [Okafor and Oduleye, 19861.ATP constricts the systemic study, Fujii and his colleagues [Hayashi et al., 19931 found vasculature of the rainbow trout [Wood, 19771. ATE ADP that the circadian motile activity of erythrophores in the and adenosine contract the coronary artery of both the red abdominal skin of the tetra tropical fish Paracheirodon rainbow and steelhead trout probably via Pl-purinocep- innesi and axeZrodi are controlled partly by ATP and tors [Small and Farrell, 1990; Small et al., 1990; Farrell adenosine. and Johansen, 19951. Within the brain of the goldfish, Carussius uuratus, The action of adenosine on the heart of the carp, the presence of adenosine binding sites has been dem- Cyprinus carpio, mimics that observed in elasmobranchs, onstrated with the characteristics of the A,, but not the actingvia a P1-purinoceptor [Cohen et al., 1981; Rotmensch Aza P1-purinoceptor subtype [Lucchi et al., 1992; Rosati et al., 19811. Similarly, in the flounder, Plutichthys Jlt.sus, et al., 19951, which is claimed to inhibit glutamate re- adenosine causes a positive inotropic effect [ Lennard and lease from the cerebellum [Lucchi et al., 19941. In two Huddart, 1989133; the trout is somewhat different in that congeneric marine fish, it has been found that the bind- adenosine and ATP are equipotent both producing nega- ing properties of the Al-receptors are different, the re- tive inotropic and positive chronotropic effects [Meghji and ceptor of the shallow-living Sebustolobus alascunus Burnstock, 1984131. exhibiting a high affinity for the Al adenosine ligand, Many fish are capable of spectacular colour changes whereas the Al-receptor in the deeper-living S. altiuelis, due to the motile activities of chromatophores, controlled exhibits a significantly lower binding affinity [Murray and both by nerves and by hormones. These include melano- Siebenaller, 19871. Low temperatures and high hydro- phore-stimulating hormone (MSH) secreted from the in- static pressures are typical of the deep sea; however, sig- termediate lobe of the pituitary giving rise to darkening, nal transduction by the Al purinoceptor system of the often antagonized by melanin-concentrating hormone bathyal deep living fish Antimura rostratu is not disrupted (MCH) which causes blanching by aggregation of pig- by deep sea conditions [Siebenaller and Murray, 19901. ments [see Fujii and Oshima, 19861. A role for purines in In goldfish exposed to warmth, the increase in locomo- the neural control of fish chematophores was first sug- tor activity is associated with increased uptake and re- gested by Fujii and Miyashita [1976], in a study of dis- lease of adenosine from cerebellar slices, suggesting a persion of melanophore inclusions in the guppy, Lebistes compensatory role for adenosine in excitatory control of reticulatus. This was confirmed later with cultured gold- motor centres [Poli et al., 19951. fish erythrophores [Ozato, 19771. Since niethylxanthines A NANC inhibitory response to electrical stimula- antagonize the darkening reaction, it was concluded that tion has been observed in the urinary bladder of the cod an adenosine receptor was involved in the responses of Gadus morhua; ATP has an excitatory effect on about half melanosomes in the siluroid catfish, ParusiEurus of the bladder preparations examined and was included 222 BURNSTOCK as a putative candidatc for the NANC transmitter [ Lundin P2-purinoceptors stimulate increases in Ca current by a and Holmgren, 19863. pathway that might involve phosphoinositide turnover There is evidence that soine fish are attracted to [Alvarez et al., 19901. It has been shown that under cer- purine compounds in a manner similar to that ofcarnivo- tain conditions of physiological strcss, such as hypoxia, rous crustaceans. Chemoreceptors on the lip ofthe puffer ATP is released from the heart [Paddle and Burnstock, fish Fog0 pundalis exhibit an especially high sensitivity 1974; Doyle and Forrester, 19851. Thus, ATP is available for ADIj and are thought to direct the fish to food sources to directly modulate activity, and indirectly after degra- [Kiyohara et al., 19751. dation to adenosine, which in itself has been found to mediate a protective influence on the frog heart against Amphibia periods of reduced calcium availability [Touraki and Evidence was presented in the early 1970's that Lazou, 19921. It has been shown that frog atria receive a ATP was a transmitter in the NANC nerves supplying NANC excitatory innervation [Donald, 19851. ATP has a the toad stomach [Burnstock et al., 1970; Satchel1 and biphasic action, initial excitation followed by inhibition Burnstock, 19711, duodenum and ileum [Burnstock et al., [Flitney et al., 19771, the excitatory effects bcing medi- 19721. ATE ADrj and AMP were shown to be released ated by Pe-purinoceptors, while the inhibitory effects are upon stiniulation of vagal NANC fibres and ATP mim- mediated by PI-purinoceptors following the degradation icked the relaxation in response to nerve stimulation. of ATP to adenosine [Burnstock and Meghji, 19811. The Evidence that ATP is the transmitter substance rcleased excitatory responses to ATP partially mimics NANC from NANC excitatory fibres in the splanchnic nerves stimulation of the frog and toad heart where it is believed supplying the small intestine of the toad was also pre- that ATP is a cotransmitter with adrenaline [Hoyle and sented, where again responses to nerve stiniulation were Burnstock, 1986; Bramich et al., 19901 acting on P2X- mimicked by ATP [Sneddon et al., 19731. Cultures ofcili- purinoceptors. ATP also has a biphasic action on the heart ated cells from the frog oesophageal epithelium and pal- of the axolotl Ambystornu inexicunurn [Meghji and Burn- ate have been used as a model for studying the role of stock, 1983bI. Unlike fish, the amphibian ventricle is sen- ATP in control of mucociliary activity. A'TP in micromo- sitive to adenosine and ATE For instance, adenosine lar concentrations increases the ciliary activity by 34- excites ventricular muscle of the toad Xenopus Zaevis fold in frequency and 4-5-fold in the rate of transport, as [Meghji and Burnstock, 1983~1but is inhibitory in the well as stimulating mucin release [Ovadiahu et al., 1988; axolotl [Meghji and Burnstock, 1983b1 whereas in the Gheber and Priel, 19943. ATP hyperpolarizes thesc frog, ATP is excitatory [Flitney and Singh, 1980; cells [Tarasiuk et al., 19951. Studies using 3,-0-(4- Burnstock arid Meghji, 19813. ATP in the niicromolar benzoyl)benzoylA1P (BzATP) as a photoaffinity label range had two types of effect on isolated myocytes from for the ATP receptor involved were claimed to suggest the frog ventricle: it acted through PI-purinoceptors af- the participation of two labelled proteins with molecular ter breakdown to adenosine to antagonize the increase masses of 46 and 96 KDa (P46 and P96) in the stimula- in Ic,,elicited by P-adrenoceptor stimulation; and directly tory effect of ATP on the ciliary beat [Gheber et al., 19951. through P2-purinoceptors (probably the P2Y-subtype) to Another study suggested that the extracellular ATP-in- increase Ici, [Alvarez et al., 19901. duccd changes in both ciliary beat frequency and mem- Descriptions of the effect of purine compounds brane fluidity are triggered by similar signal transduction on amphibian vascular preparations are somewhat lim- pathways [Alfkihel et al., 19961. ited. However, a prejunctional adenosinc receptor Adenosine exerts effects on the amphihian heart in revealed to be an A,-adenosine receptor has been iden- a nianner similar to its effect upon the mammalian heart, tified, which inhibits sympathetic nerve activity to the having negative chronotropic and inotropic effects, mim- frog cutaneous muscle arterioles resulting in vasodilata- icking the response to ACh by slowing the heart. This tion [Fuglsang and Crone, 1988; Fuglsang et al., 19891. has been ohserved in the hearts of the frogs, Ram ridi- In addition, stimulation ofvagal NANC fibres in the toad bumla [Lazou and Beis, 19873,R. pipiens [Hartzell, 19791, Bufo rnaiiiaus mediates a fall in vascular resistance, al- R. temporuriu [Burnstock and Meghji, 19811, and R. though the transmitter is as yet unidentified [Campbell, cutesbiawu [Yatnni et al., 1978; Goto et al., 19811. In con- 19711. In a recent study of purinoceptors in the aorta of trast, ATP lias excitatory effects, increasing the force and the frog, Runa ternporuria, Knight and Burnstock [1995h] rate of the heart beat [Cook et al., 1958; Goto et al., 1977; concluded that there appears to be a novel subclass of Burnstock arid Meghji, 1981; Hoyle and Biirnstock, 1986; PI-purinoceptor mediating vasodilatation which, like Bramich et al., 19901. Currents activated by extracellular the rat A:, subclass, is not blocked hy niethylxanthines; ATP were studied on single voltage clamped bullfrog they also identified a P2-purinoceptor that mediates atrial cells; two ATP-activated conductances were dem- vasoconstriction that resembles a P2X subtype in onstrated [Friel and Bean, 19881. In frog ventricular cells, ternis of agonist potencies and is antagonized by ONTOCENY AND PHYLOGENY OF PURINOCEPTORS 223 PPADS. However, no evidence for a P2Y-purinoceptor Silinsky, 1980; Ribeiro and SebastiHo, 1987; Branistcanu mediating vasodilatation was found. et a]., 1989; Hirsh et al., 1990; SebastiHo and Ribeiro, Purine compounds also have effects on preparations 1990; Bennett et al., 1991; Silinsky and Solsona, 1992; from amphibian tissues other than those of the gas- Hunt and Silinsky, 19931. Examination of the actions of trointestinal and cardiovascular systems. Vagal stimula- adenosine analogs suggested that this presynaptic PI-pu- tion of the visceral muscle of the lung of Bufo rnarinus is rinoceptor may be of the Al-subtype [Barry, 19901, al- purely inhibitory and the transmitter unknown, although though this has been debated [SebastiHo and Ribeiro, ATP was proposed as a candidate [Campbell, 19711 and 19891. Later it was shown that ATP was released together it had been shown that ATP caused relaxations of the lung with ACh from motor endings [Silinsky and Hubbard, preparation [Meves, 19531. ATP has recently been shown 1973; Silinsky, 19751 where it could then act as a to activate membrane current in frog Schwann cells postjunctional potentiator of ACh action, and following [Vinogradova et al., 19941, perhaps playing a role in neuro- breakdown by ectoenzymes to adenosine [see Cunha and glial interactions, since perisynaptic Schwann cells at the Sebastibo, 1991; Cascelheira and SebastiHo, 19921, to act frog neuromuscular junction showed increases in intrac- prejunctionally to inhibit ACh release [Silinksky and ellular calcium during motor nerve stimulation, an effect Redman, 19961. mimicked by local application of ATP [Jahromi et al., ATP has been implicated as a synaptic transmitter 1992; Robitaille, 19951. Injections of ATP into the third in both sympathetic and sensory ganglia. After an early ventricle of the mud puppy, Necturus muculosus, elic- paper where high concentrations of adenine nucleosides ited dose-related increases in thermal tolerance [Ritchart and nucleotides were shown to have depressant and and Hutchison, 19861. Adenosine inhibits a-melanocyte- hyperpolarising actions on both dorsal and ventral root stimulating hormone (a-MSH) from frog pituitary neurons in isolated hemisected perfused toad spinal cords melanotrophs, suggesting that Al-purinoceptors may play [Phillis and Kirkpatrick, 19781, ATP was shown to clepo- a physiological role in the regulation of hormone release larize bullfrog sympathetic ganglion cells [Nakamura et from the intermediate lobe of the pituitary [Chartrel et al., 1974; Siggins et al., 19771. ATP probably acts by de- al., 19911. An inhibitory action of adenosine on electrical creasing K+ conductance, including the M -current; ATP activity of frog pituitary melanotrophs mediated via Al- also depressed the maximum amplitude of action poten- purinoceptors has been reported [Mei et al., 19'341. ATP tial after-hyperpolarizations and it was suggested that ATP regulates a quinidine-sensitive K+ conductance in single released with ACh from presynaptic nerve terminals may proximal tubule cells isolated from frog kidney [Lynch act as a modulator of nicotinic transmission [Akasu et al., and Hunter, 1994; Robson and Hunter, 19951. P2Y-re- 1983b]. ATP inhibits calcium current in frog sympathetic ceptors on A6 epithelial cells derived from renal distal neurons [Elmslie, 19921. Silinsky and Ginsborg [1983] tubules of Xenopus Zaevis mediate increases in intracel- claimed that inhibition of ACh release from pregangli- lular Ca2+concentrations by releasing Ca2+froni intrac- onic nerves supplying neurons in the ninth lumbar sym- ellular stores [Mori et al., 19961. pathetic chain ganglion of the frog, Ranu pipiens, was Many years ago, Buchthal and Folkow [1944] in- largely by ATP itself rather than by adenosine after break- jected ATP into the sciatic artery supplying the gastroc- down of ATE However, in keeping with the evidence for nemius muscle of the frog and reported tetanus-like synaptic transmission at the skeletal neuromuscular junc- contractions; they also observed that the sensitivity of tion, ATP was later shown to increase the sensitivity of the the preparation to ACh was greatly increased by previ- nicotinic ACh receptor in bullfrog ganglia cells and it was ous application of ATE This postjunctional potentiation suggested that ATE perhaps via a P2-purinoceptor, had this of ACh responses by ATP was later confirmed in bullfrog effect by acting on an allosteric site of the ACh-receptor- sympathetic ganglia [Akasu et al., 1981, 1983a,b] and in ionic channel complex [Akasu and Koketsu, 19851. developing Xenopus neuromuscular synapses in culture The concentration-dependence and kinetics of ionic [Igusa, 1988; Fu and Poo, 1991; Fu et al., 1993; Fu, 1994; currents activated by ATP were studied in voltage- Fu and Huang, 19941. The effect of ATP is apparently clamped dorsal root ganglion cells from bullfrogs [Bean, mediated by the activation of cytosolic protein kinases 1990; Bean et al., 19901. About 40% of the neurons re- and requires the influx of Caz+through the plasma mem- sponded with an increase in membrane conductance, but brane. In addition, a further purinergic involvement in showed rapid desensitization, typical of the P2X3-pu- transmission at the frog neuromuscular junction was rec- rinoceptor recently described in rat dorsal root nerves ognized, namely modulation of ACh release via [Chen et al., 1995; Lewis et al., 19951. Ethanol was shown prejunctional P1-purinoceptors. Both end plate poten- to inhibit the ATP-activated current in dorsal root gan- tials (epps)in response to nerve stimulation and sponta- glion cells, perhaps by increasing the apparent dissocia- neous miniature epp's were reduced by adenosine tion constant of the ATP receptor [Li et d., 19931. In a [Ginsborg and Hirst, 1972; Ribeiro and Walker, 1975; later study, Akasu and his colleagues [Tokimasa et al., 224 BURNSTOCK

19931 showed with dissociated hillfrog dorsal root gan- diating vasodilatation and P2-purinoceptors mediating glion cells that, whereas in small C-cells ATP (1-10 pM) vasoconstriction are present. However, in contrast to activated a sodium-potassium current, in large A-cells mammalian aorta, both P2X- and P217-subtypesmediate (approx. 65 pin in diameter) ATP inhibited M-current. vasoconstriction; there was no evidence for vasodilata- In some bullfrog primary afferent neurons, ATP revers- tion by ATP or its analogues. In contrast, the portal vein ibly augmented GABA-induced depolarizations [Morita of the rainl>owlizard, Agarnu agarna, dilated in the pres- et a]., 19841. ence of ATP [Ojewole, 1983bI. Occupation of the P2- Sincc spontaneous ACh release is known to regu- purinoceptor led to synthesis of prostanoids as in late the clevelopment of contractile properties of the inammals [Knight and Burnstock, 1995al. postsynaptic muscle cell [Kidokoro and Saito, 19881, the The visceral smooth muscle of the lung of the snake, authors suggest that ATP coreleased with ACh niay serve Tharnnophis sp., is described as having NANC/puriner- as a positive trophic factor at developing rieuroniuscular gic innervation [Smith arid Macintyre, 19791, although synapses. there is no evidence of the involvement of ATP or ad- Xenopus oocyte has been used in expression clon- enosine in the response. In the bladder of the sleepy ing of purinoceptors [Lotan et al., 1982, 1985; Wellb et lizard, Trachysuurus rugcisa, an atropine-resistant con- al., 1993; Chen et al., 1995; Lewis et al., 1995; Bo et al., traction in response to nerve stimulation has been found. 19951, but the follicle cells contain endogenous pu- athough the transmitter substance has not been identi- rinoceptors [King et al., 1996a,b].A receptor for adenos- fied [Burnstock and Wood, 19671. ine was the first to be reported [Lotan et al., 1985; Dascal et al., 19851 which appears to be a novel subtype [King et Birds al., 1996al. P2-purinoceptor activated inward currents are An adenosine receptor has 1)cen identified in the also present [King et al., 19961-33. The actions of purines embryonic chick heart [Hatae et al., 1989; Blair et al.. at these receptors niay be involved in the sequence of 19891; it appears to be an Al-receptor, which can be down- cellular events that occur in early development [see Jessus regulated by exposure to R-PIA [Shryock et al., 19891. et al., 19891. Low concentrations of extracellular ATE ATP is a potent dilator of vessels in the duck foot. present in the perilymphatic compartment of the semi- where doses of 1.9-19 nmol produces falls in perfusion circular canal of the frog, Rana pipiens, appears to play a pressurc comparable to those produced by stimulation role in vestibular physiology; a P2Y subtype of purinoccp- of dorsal metatarsal nerves [McGregor, 1979; Bell and tor seems to be involved and Reactive Blue 2 and suramin Rome, 19841. ATP has also been shown to cause selec- antagonize the responses [Auhert et al., 1994, 19951. tive dilatation of arterio-venous shunts in the foot of the chicken [Hillmaii eta]., 19821. Since the feet ofbirds form Rept i I ia an area of skin devoid of insulative feathers, change in An excitatory NANC innervation has been identi- blood flow is used to regulate body heat as well as pre- fied in the ileum of the lizard Tiliqua rugosu, stimulation venting freezing of the foot, so that purinergic receptors of which can be mimicked by ATP [Burnstock et al., 1972; may play a part in this mechanisni. Sneddon et a]., 19131; however the subtype of P2-pu- There is evidence for P2-purinoceptors in differ- rinoccptor is not known. An excitatory effect of KIP has ent preparations of bird gut. The oesophagus of the also been noted in the rectum of the 1izardAgarna agarna chicken contracts to ATP via a P2-piirinoceptor [Bartlet, [Ojewole, 1983a; Savage and Atanga, 19851but again the 19741, as does the rectum [Bartlet, 1974; Meldrum and subtype of the purinoceptor has not been identified. Burnstock, 19851. a,P-MeATP also causes a contraction There have been few studies of purinoceptors in of the chicken rectum and is able to desensitize the exci- the cardiovascular system of reptiles. Wedd and Fenn tatory response to stimulation of Rernaks nerve, indicat- [ 19331 reported variable responses to adenosine in the ing that P2X-purinoceptors may be involved in purinergic heart of the turtle PAMP>ADP= ATE supple- Interestingly, ATP has also been shown to trigger mented with the use of selective antagonists, such as 8-PT. phosphoinositide turnover in chick rnyotubes [Hiiggblad However, there are few studies of P1-purinoceptor sub- and Heilbronn, 1987, 19881, perhaps suggesting that P2Y- types in invertebrate groups partly because identifica- as well as P2X-purinoceptors are present. The later dem- tion of purinoceptor subtypes has been hindered by the onstration of multiple responses in chick myotubes [Hume lack of activity of the available agonists and antagonists. and Thomas, 1988; Eriksson and Heilbronn, 19891 is con- Despite these limitations, the first record of suhclasses sistent with this possibility. The responses to ATP show of P1-purinoceptors into A, and A2 subtypes has heen rapid desensitization [Thomas and Hurne, 199Oal which is claimed in molluscs. Adenosine agonists such as NECA, typical of the P2XI and P2X3 subclasses of the P2X- PIA, CGS 21680, and CPA, which are selective for sub- ionotropic purinoceptor family [see North, 19961. In more classes of mammalian adenosine receptors, are found to recent analyses of the ion channels involved in ATP-medi- be inert in most invertebrates. Hopefully, some of the ated responses of chick skeletal muscle, excitation has been new selective agonists and antagonists for Al, AzA, AzB, shown to be due to a simultaneous increase in membrane and A3 subtypes [Jacobson et al., 19961 will be applied to permeability to sodium, potassium, and chloride ions, and invertebrate and lower vertebrate preparations. Bind- that only a single class of excitatory ATP-activated channels ing studies of the Al-selective ligand [3H]cyclo- are involved which do not select by charge, i.e., they con- hcxyladenosine (CHA) in brain membranes were not duct both cations and anions [Thomas and Hume, 199Ob; positive in molluscs and arthropods, although they were 19931. The order of potency for agonists at this receptor in hagfish [Siebenaller and Murray, 19861. was ATP =ATpyS =2meSATP >2 '-deoxy-ATP=3 '-deoxy- There are many examples of the presence of P2- ATP>ATP-OPO, =ADP and both 2 ',3 'dialdehyde-ATP purinoceptors in a variety of tissues from many inverte- and 4,4 '-diisocyanatostilbene-2,2 '-disulphonic acid brate groups. Identification relies predominantly on the (DIDS) were potent irreversible inhibitors; 8-Br-ATPwas selective or more potent effect of ATP compared with ad- a weak antagonist,while 2 ',3 '-dialdehyde-ATP and DIDS enosine and the use of PI-purinoceptor antagonists to rule were potent irreversible inhibitors [Thomas et al., 19911. out responses to ATP due to adenosine resulting from ex- It has been suggested that extracellular adenine tracellular breakdown of ATE Identification of subtypes is nucleotides may be involved in the PO2-dependentregu- again hindered since P2-receptor antagonists developed for lation of red cell metabolism in late chick embryos [Koller use in mammalian systems [see Fredholm et al., 19941 some- et al., 19941. P1(A2)purinoceptor mediated stimulation times lack activity in invertebrate tissues. For instance, in of cyclic AMP in cultured chicken pineal cells has been the Sea anemone, Reactive Blue 2 has agonist properties reported [Falcon et al., 19951. Adenosine induced apo- [Hoyle et al., 19891 and in identified neurons of the leech, ptosis in chick embryonic sympathetic neurones suramin failed to block the activity of ATP and behaved as [Wakade et al., 19951. Adenosine has been shown to an agonist [Backus et al., 19941 although it has been shown modulate calcium currents in postganglionic neurones recently that suramin is not an antagonist at P2&- and P2&)- of cultured avian ciliary ganglia [Bennett and Ho, purinoceptor subtypes [Bo et al., 1995; Buell et al., 19961. 1991; Bennett et a]., 19921. Another problem in trying to distinguish P2X and P2Y subtypes is that the relative potencies of agonists depends to Speculations About the Evolution of some extent on the presence or absence of powerful Purinoceptor Subtypes ectoATPases [see Kennedy and Lee 1995; Kennedy et al., While it must be recognized that it is dangerous to 19961. Thus, in the presence of Camg ATPase inhibitors look for an evolutionary pattern in the development of or in single cell preparations, the classical P2X- and P2Y- 226 BU RNSTOCK

TABLE 3. Summary of Reports of P1 and P2 Purinoceptors and, in Some Preparations, Their Subtypes in Various Tissues From Bacteria, Protozoans, Coelenterates, and Molluscs

PI Purinoceptors P2 Purinoceptors Phyl uin Tissueiactivity PI (not subtyped) A, A2 A3 P2 (not subtyped) P2X P2Y Bacteria Inhibition of growth Initiation of sporulation v Regulation of binding of enterotoxin J Protozoa Inhibition of amoeboid movement J Increase of contractile vacuole output J Cell aggregation v J Motility increase of ciliated paramecium J Herniation J Cytoskeletal organization J Inhibition of growth of pedal disc J Coelenterates Contraction of anemone pedal disc J J Maturation of nematocysts v Ciliary reversal in ctenophores v Molluscs Activation of snail suboesophageal neurons v Neuromodulation of transmitter release from pedal ganglion of Mytilus Excitation of heart J J Contraction of snail rectum and oesophagus J Rupture of secretory glands of slug J

(i) = inhibition; (ej = excitation. purinoceptor potency series [BumstockandKennedy, 19851 tehrates [see Ziganshin et al., 19941, this must be taken into of a,P-meATP>ATP>2meSATP and 2meSATP> >ATP > account in the interpretation of P2 agonist potency series a,P-meATT: respectively, need to be modified for P2X- in the lower animals. Despite these problems, there are purinoceptors: ATP=2meSATP> a,P-nieATPand for P2Y- records of fast P2X-purinoceptors involving ion channels purinoceptors: 2meSATP>ATP> a,PmATE Since little is in the nervous system ofmolluscs, annelids, and arthropods. known about ecto-ATPases in invertebrates and lower ver- One of the complications is the emerging evidence

TABLE 4. Summary of Reports of P1 and P2 Purinoceptors and, in Some Preparations, Their Subtypes in Various Tissues From Annelids, Arthropods, and Echinoderms

PI Purinoceptors P2 Purinoceptors

Phylum Tissue/activity PI (not subtyped) A, A1 A3 P2 (not subtyped) P2X P2Y

Annelids Depolarization of leech neurons J Stimulation of salivary cells J Arthropods Crustaceans Stimulation of lobster olfactory and J gustatory chemoreceptors Feeding behaviour J (el Inhibition of crab heart J (i) Stirnulation of lobster intestinal neurons J Insects Initiation of the gorging reflex in blood suckers: tsetse fly rc stable fly v Feeding stimulation in flea and tick J Stimulation of fat body of silkworm v Echinoderms Relaxation of gastric ligament of starfish J J Relaxation of body muscles of sea cucumber J Contraction of rectum of sea urchin J I/ Contraction of spine muscles of sea urchin J Inhibition of growth of fertilized starfish eggs J Modulation of sea urchin flagellar motility J

(i) = inhibition; (ej = excitation ONTOGENY AND PHYLOGENY OF PURINOCEPTORS 227

TABLE 5. Summary of Reports of PI and P2 Purinoceptors and, in Some Preparations, Their Subtypes in Various Tissues From Cyclostomes, Elasmobranch, Coelenterate, and Teleost Fishes

PI Purinoceptors P2 Purinoceptors

Vertebrates Tissue/activity PI (not subtyped) A, A2 A3 P2 (not subtyped) P2X P2Y

Fish Cyclostomes Dilatation of brachial vessels of hagfish I/ L Elasmobranchs Inhibition of intestinal motility in v dogfish and ray Contraction of stomach J Stimulation of rectal gland of shark Dogfish aorta Coronary artery of: Skate Mako shark Electric organ Teleosts Cod, stickleback and flounder intestine Carp and goldfish intestine Rectum of flounder Stomach of stickleback Gill vessels of: Trout J (c) Cichlid Systemic vessels of trout Heart of carp and flounder and trout Melanophore dispersion in medaka v Brain of goldfish (temperature J control and locomotor activity) Excitation of bladder v

(c) = constrict/contract; (d) = dilateirelax. for a P2-purinoceptor subtype, both in lower animals, lutionary precursors of the pulmonary vasculature; al- and in certain mammalian cell lines (e.g., C6 glioma cells though in mammalian pulmonary systems, such as the [Boyer et al., 19931; DDT,-MF2-smooth muscle cells rabbit, adenosine is a potent vasodilator, acting via an A>- [Sipma et al., 19941 and in mouse C2C12 myotubes receptor [Pearl, 19941, there are also reports of vasocon- [Henning et al., 1993a,b], which operates via an adeny- strictor actions of adenosine in the pulmonary bed late cyclase second messenger system, since one of the [Biaggioni et al., 1989; Neely et al., 19911. original criteria for distinguishing PI- from P2-purinocep- P2X-purinoceptors have been described in teleost tors was adenosine action through adenylate cyclase fish; separate P2X- and P2Y-purinoceptor subtypes are [Burnstock, 1978bl. It is possible that the primitive P2- well represented in amphibians, reptiles, and birds. Car- purinoceptor acted via an adenylate cyclase transduction diovascular P2-purinoceptors have also been identified system in parallel with PI-purinoceptors and only later in lower vertebrates which parallel those described in diverged to act via inositol trisphosphate second mes- mammals [Ralevic and Burnstock, 19911 For example, senger systems or ligand-gated ion channels. ATP causes vasoconstriction of'the systemic vasculature Adenosine has potent cardiovascular actions on sev- of the trout Salmo gairdneri [wood, 19771. ATP constricts eral fish groups, including vasodilator and vasoconstric- the coronaiy artery of the trout Oncorhynchus mykiss, tor actions [see Nilsson and Holmgren, 19921, with many being equipotent with ADE but more potent than ad- striking similarities to the effect of adenosine on mam- enosine, indicating a P2-purinoceptor [Small and Farrell, malian cardiovascular systems [see Collis, 1989; Olsson 19901. The vascular rings are described as being endot- and Pearson, 19901. Al and A2 subclasses of Pl-purinocep- helium-free and may therefore correspond to the vaso- tor first appear in elasmobranch fish; A, receptors have constrictor P2X-purinoceptor found on mammalian been described in amphibians. Studies of the action of vascular smooth muscle. adenosine on the gill vasculature of teleost fish, all re- With the exception of the mussel and the turtle, vir- port vasoconstriction, e.g., as in the trout Salmo gaird- tually every examined species of invertebrate and lower neri [Colin and Leray, 1979; Colin et al., 19793 and tropical vertebrate heart responded to adenosine or ATE and of- cichlid Oreochrornas niloticus [Okafor and Oduleye, ten both, frequently mimicking the effect of adenosine 19861. Fish ventral aorta and brachial vessels are the evo- and ATP on the mammalian heart. There is considerable 228 BURNSTOCK

TABLE 6. Summary of Reports of P1 and P2 Purinoceptors and, in Some Preparations, Their Subtypes in Various Tissues From Amphibians, Reptiles, and Birds

PI f'urinoceptors P2 Purinoceptors

Tissue/activity PI (not subtyped) A, A2 A3 P2 (not subtyped) P2X P2Y

Amphibians Toad stomach Frog heart Frog isolated ventricular cells Frog ventricle v Prejunctional modulation of sympathetic v nerve activity Frog aorta Toad lung Increases in beat frequency of ciliary cells from frog palate and oesophagus Activation of membrane currents in v Schwann cells Increase in thermal tolerance after v brain injections Regulation of hormone release from pituitary Proximal tubules of frog kidney Modulation in sympathetic ganglia and neuromuscular junction Toad spinal cord Bullfrog dorsal root ganglia Xenopus oocyte follicular cells v v Semicircular canal of frog Reptiles Lizard ileum and rectum Snake aorta Lizard portal vein Birds Embryonic chick heart Vessels of duck foot Chicken rectum Chick myotubes v Stimulation of chicken pineal cells v Ciliarv ganglia v

(i) = inhibition/relaxation/dilatation; (e)= excitation/contraction. evidence for P2-purinoceptors on the amphibian atria and potent than ATP but may be acting via a P2-purinoceptor. ventricle. ATP causes positive inotropic effects on frog GTP has been found to modulate ACh-induced depolar- atrial [Goto et al., 1977; Burnstock and Meghji, 19811and ization of Buccinurn undntum proboscis smooth muscles, ventricular muscle [Flitney et al., 1977; Flitney and Singh, whereas ATP and adenosine are without activity [Nelson 1980; Burnstock and Meghji, 19811, the excitatory ATP and Huddart, 19941. Various other purine or pyrimidine responses in the atria of the frog is inhibited by a,p- triphosphates including cytidine, inosine, and xanthosiiie nieATE suggesting the presence of P2X-purinoceptors (CTe ITE and XTP) stimulate chenioreceptors of crusta- [Hoyle and Burnstock, 19863. ceans [Carr et al., 1986, 19871; similarly, the monophos- Amphibian bladders studied so far would appear phates of inosine, guanosine, and cytidine (IME GMe to possess a contractile P2X-purinoceptor with similar and CMP) together with the triphosphates ITE GTE CTe characteristics to those of mammalian urinary bladders and UTE all stimulate gorging of blood-feeding insects [see Hoyle and Burnstock, 1985,19921. These studies also [Galun and Margalit, 1969; Friend and Smith, 1982; Dadd provide evidence for purinergic neurotransinission in the and Kleinjan, 19851, as does the tetraphosphate of acl- urinary bladders of amphibians. enosine [Galun et al., 1963,1988; Smith and Friend, 19761. There is evidence that purines other than adenos- ATP and adenosine stimulate the hearts of two molluscs, ine and ATP and also pyrimidines have activity on some as does uridine, UDE and UTE cytidine, CME CDE and invertebrate and lower vertebrate tissues. The purine CTl? In contrast, GMP and GDP are inhibitory implying guanosine 5 '-monophosphate (GMP) acts in a similar separate receptors [S.-R6zsa, 19681. Actions of pyrim- manner as ATE by modulating calcium conductance in idines and purines other than adenosine and ATP have leech salivary glands [Wuttke and Berry, 19931; it is less also been described in lower vertebrates. 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