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Historical Review: ATP As a Neurotransmitter

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Historical Review: ATP As a Neurotransmitter ARTICLE IN PRESS Review TRENDS in Pharmacological Sciences Vol.xx No.xx Month2006 Historical review: ATP as a neurotransmitter Geoffrey Burnstock Autonomic Neuroscience Centre, Royal Free & University College Medical School, Rowland Hill Street, London NW3 2PF, UK Purinergic signalling is now recognized to be involved in describing the physiological significance, pharmacological a wide range of activities of the nervous system, action and therapeutic use of adenylyl compounds in including neuroprotection, central control of autonomic humans was published in 1957 by Boettge et al. [8]. functions, neural–glial interactions, control of vessel Subsequently, an influential hypothesis was proposed by tone and angiogenesis, pain and mechanosensory Berne [9], who postulated that adenosine was the transduction and the physiology of the special senses. physiological mediator of the coronary vasodilatation In this article, I give a personal retrospective of the associated with myocardial hypoxia. An alternative discovery of purinergic neurotransmission in the early hypothesis was proposed later [10], namely that ATP 1970s, the struggle for its acceptance for w20 years, the released from endothelial cells during hypoxia and shear expansion into purinergic cotransmission and its event- stress acted on endothelial P2 receptors, resulting in the ual acceptance when receptor subtypes for ATP were release of nitric oxide (NO) and subsequent vasodilatation; cloned and characterized and when purinergic synaptic adenosine participated only in the longer-lasting com- transmission between neurons in the brain and periph- ponent of reactive hyperaemia (increased blood flow). eral ganglia was described in the early 1990s. I also Details of various early studies that reported extracellular discuss the current status of the field, including recent roles of ATP are summarized in a historical review interest in the pathophysiology of purinergic signalling published in 1997 [11]. In this article, I review the later and its therapeutic potential. research, in which I have been an active participant. ‘Non-adrenergic, non-cholinergic neurotransmission’ Early history After completing studies of noradrenaline (NA)- and ACh- The diverse range of physiological actions of ATP was mediated responses of the guinea-pig taenia coli in Edith recognized relatively early. For example, in 1929, Drury Bu¨ lbring’s laboratory at the Department of Pharmacology, and Szent-Gyo¨rgyi [1] demonstrated the potent extra- Oxford [12], I moved to Melbourne, Australia. There, I set cellular actions of ATP and adenosine on the heart and up the sucrose gap apparatus in my laboratory for coronary blood vessels. The published follow-up studies of recording continuous correlated changes in electrical and the cardiovascular actions of purines during the next 20 mechanical activity of smooth muscle [13]. Graeme Camp- years were reviewed by Green and Stoner in 1950 in a bell and Max Bennett were working with me, and one day book entitled ‘Biological Actions of the Adenine Nucleo- in 1962 we decided to look at the direct response of the tides’ [2]. In 1948, Emmelin and Feldberg [3] demon- smooth muscle of the guinea-pig taenia coli after blocking strated that intravenous injection of ATP into cats caused the responses of the two classical neurotransmitters ACh complex effects that affected both peripheral and central and NA. We expected to see contractions in response to mechanisms. Injection of ATP into the lateral ventricle direct stimulation of smooth muscle, perhaps associated produced muscular weakness, ataxia and a tendency of with depolarization, but remarkably we obtained rapid the cat to sleep. Application of ATP to various regions of hyperpolarizations and associated relaxations in response the brain produced biochemical or electrophysiological to single electrical pulses. This was an exciting moment changes [4]. Holton presented the first hint of a and we all felt instinctively that this unexpected result transmitter role for ATP in the nervous system by was going to be important. Later we, and others, showed demonstrating the release of ATP during antidromic that tetrodotoxin, which had just been discovered in Japan stimulation of sensory nerves supplying the rabbit ear and which blocked nerve conduction but not muscle artery [5]. Buchthal and Folkow recognized a physiologi- responses, abolished these hyperpolarizations and we cal role for ATP at the neuromuscular junction, finding realized that we were looking at inhibitory junction that acetylcholine (ACh)-evoked contraction of frog skel- potentials (IJPs) in response to a non-adrenergic, non- etal muscle fibres was potentiated by exposure to ATP [6]. cholinergic (NANC) inhibitory neurotransmitter [14,15]. Furthermore, presynaptic modulation of ACh release from At about the same time, Martinson and Muren [16] in the neuromuscular junction by purines in the rat was Sweden recognized the existence of NANC inhibitory reported by Ginsborg and Hirst [7]. An extensive review neurotransmission in the cat stomach. A detailed study of Corresponding author: Burnstock, G. ([email protected]). the mechanical responses of the taenia coli to stimulation of intramural NANC and sympathetic nerves was carried www.sciencedirect.com 0165-6147/$ - see front matter Q 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2006.01.005 ARTICLE IN PRESS 2 Review TRENDS in Pharmacological Sciences Vol.xx No.xx Month2006 out while I was on sabbatical leave at the School of felt that ATP was established as an intracellular energy Pharmacy in London, working with Mike Rand [17]. source involved in various metabolic cycles and that such a ubiquitous molecule was unlikely to be involved in The ‘purinergic’ hypothesis extracellular signalling. However, ATP was one of the Several years later, after many experiments, we published biological molecules to first appear and, therefore, it is not a study that suggested that the NANC transmitter in the surprising that it should have been used for extracellular, guinea-pig taenia coli and stomach, rabbit ileum, frog in addition to intracellular, purposes early in evolution stomach and turkey gizzard was ATP [18]. The exper- [21]. The fact that potent ectoATPases were described in imental evidence included: mimicry of the NANC nerve- most tissues in the early literature was also a strong mediated response by ATP; measurement of the release of indication for the extracellular actions of ATP. Purinergic ATP during stimulation of NANC nerves with luciferin– neurotransmission is now generally accepted [22,23] and a luciferase luminometry; histochemical labelling of sub- volume of ‘Seminars in Neuroscience’ was devoted to populations of neurons in the gut with quinacrine, a purinergic neurotransmission in 1996 [24]. fluorescent dye known to label selectively high levels of ATP bound to peptides; and the later demonstration that Purinergic cotransmission the slowly degradable analogue of ATP, a,b-methylene Another concept that has had a significant influence on ATP (a,b-meATP), which produces selective desensitiza- our understanding of purinergic transmission is cotrans- tion of the ATP receptor, blocked the responses to NANC mission. I wrote a Commentary in Neuroscience in 1976 nerve stimulation. Soon after, evidence was presented for entitled: ‘Do some nerves release more than one trans- ATP as the neurotransmitter for NANC excitatory nerves mitter?’ [25]; this challenged the single neurotransmitter in the urinary bladder [19]. The term ‘purinergic’ was concept, which became known as ‘Dale’s Principle’, even proposed in a short letter to Nature in 1971 and evidence though Dale himself never defined it as such. The for purinergic transmission in a wide variety of systems commentary was based on hints about cotransmission in was presented in Pharmacological Reviews [20] (Figure 1). the early literature describing both vertebrate and This concept met with considerable resistance for many invertebrate neurotransmission and, more specifically, years. I believe that this was partly because biochemists with respect to purinergic cotransmission, on the surpris- ing discovery by Che Su, John Bevan and me, while I was on sabbatical leave at University of California, Los Angeles in 1971, that ATP was released from sympathetic nerves supplying the taenia coli and from NANC ATP Large, opaque inhibitory nerves [26]. Ironically, when Mollie Holman vesicle and I published the first electrophysiological study of ATP containing ATP sympathetic neuromuscular transmission in the vas resynthesis Adenosine deferens [27], we recorded excitatory junction potentials (EJPs) that were not blocked by adrenoceptor antagonists (Figure 2a). It was not until O20 years later, when Peter P1 Sneddon joined my laboratory in London, that we showed purinoceptor that the EJPs were blocked by a,b-meATP (Figure 2b) [28], Adenosine uptake a compound shown by Kasakov and Burnstock to be a ATP selective desensitizer of P2X receptors [29]. This clearly ATPase supported the earlier demonstration of sympathetic ADP cotransmission in the vas deferens in the laboratory of Dave Westfall [30], following the report of sympathetic AMP cotransmission in the cat nictitating membrane [31]. 5′-Nucleotidase Purinergic cotransmission was later described in the rat tail artery [32] (Figure 2d) and in the rabbit saphenous Adenosine Circulation P2 Adenosine artery [33] (Figure 2c). NA and ATP are now well purinoceptor deaminase established as cotransmitters in sympathetic nerves Inosine
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