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1521-0111/90/5/649–673$25.00 http://dx.doi.org/10.1124/mol.116.104752 MOLECULAR Mol Pharmacol 90:649–673, November 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics

MINIREVIEW—A LATIN AMERICAN PERSPECTIVE ON -COUPLED RECEPTORS

The H3 : Structure, Pharmacology, and Function

Gustavo Nieto-Alamilla, Ricardo Márquez-Gómez, Ana-Maricela García-Gálvez, Guadalupe-Elide Morales-Figueroa, and José-Antonio Arias-Montaño Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados (Cinvestav-IPN), Downloaded from Zacatenco, Ciudad de México, México Received April 15, 2016; accepted August 24, 2016

ABSTRACT molpharm.aspetjournals.org Among the four G protein–coupled receptors (H1–H4)identified characteristics of the H3R, namely, its structure, constitutive as mediators of the biologic effects of histamine, the H3 activity, isoforms, pathways, regional dif- receptor (H3R) is distinguished for its almost exclusive expres- ferences in expression and localization, selective , sion in the nervous system and the large variety of isoforms antagonists and inverse agonists, dimerization with other generated by alternative splicing of the corresponding mRNA. receptors, and the main presynaptic and post- Additionally, it exhibits dual functionality as and synaptic effects resulting from its activation. The H3Rhas , and this enables H3Rs to modulate the hista- attracted interest as a potential target for the treatment of minergic and other neurotransmitter systems. The cloning of the several important neurologic and psychiatric disorders, such H3R cDNA in 1999 by Lovenberg et al. allowed for detailed as Alzheimer and Parkinson , Gilles de la Tourette studies of its molecular aspects. In this work, we review the syndrome, and . at ASPET Journals on October 1, 2021

Introduction morphologic characterization of histamine-producing proved the existence of a system in the mam- In 1910, Sir Henry Dale and colleagues (Dale and Laidlaw, malian (Fig. 1). 1910) isolated histamine from ergot and later found that it had a effect on from the gut and the , caused vasodepression, stimulated cardiac The Brain Histaminergic System contractility, and induced a -like syndrome when in- Histamine-synthesizing neurons are located in the hypo- jected into animals. In 1920, Popielski demonstrated that thalamus tuberomamillary nucleus (TMN), with ∼4500 neu- histamine stimulated gastric acid secretion, and in 1927, the rons found in the TMN and ∼64,000 neurons in the human was isolated from the and the , evidencing TMN. These neurons send diffuse projections to the entire that it was a natural constituent of the body (reviewed by (CNS) through three major path- Parsons and Ganellin, 2006). ways, two ascending bundles that innervate the forebrain Although histamine was detected in the brain in 1919 by structures and one descending bundle reaching the spinal John J. Abel, its role as a neuromodulator became evident only cord (Watanabe et al., 1984; Airaksinen and Panula, 1988; several decades later; using against the amine and Haas et al., 2008). its synthesizing enzyme, decarboxylase (HDC), the Histaminergic neurons have a resting membrane potential of about 250 mV and spontaneously fire action potentials at ’ Research in J.-A. A.-M. s laboratory is supported by Cinvestav and the 2.1 6 0.6 Hz with a marked circadian rhythmicity, that is, Mexican Council for Science and Technology (Conacyt). 1 dx.doi.org/10.1124/mol.116.104752. more active during wakefulness. A noninactivating Na

ABBREVIATIONS: aa, amino acids; A2AR, A2A receptor; ACh, ; AD, Alzheimer’s ; CHO, Chinese hamster ; CNS, central nervous system; CT, carboxyl terminus; D1R, D1 receptor; D2R, dopamine D2 receptor; ECL, extracellular loop; 5-HT, 5-hydroxytriptamine (); GIRK, G protein–gated inwardly rectifying K1 channel; GPCR, G protein–coupled receptor; GTS, Gilles de la

Tourette syndrome; H1R, ; H2R, ; H3R, ; H4R, ; HDC, ; hH3R, human H3R; ICL, intracellular loop; IP3, inositol-1,4,5-trisphosphate; MAPK, mitogen-activated protein kinase; MCH, melanin-concentrating ; MSN, striatal medium-sized spiny ; NHE, Na1/H1 exchanger; PD, Parkinson’s disease; PKA, ; PKC, protein kinase C; PLC, ; PTX, pertussis toxin; RT-PCR, reverse-transcription polymerase chain reaction; SN, substantia nigra; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; TM, transmembrane; TMN, tuberomammillary nucleus.

649 650 Nieto-Alamilla et al.

transporter, although astrocytes take up histamine with low affinity (Km 0.56 mM and 4.0 mM) through the activity of the plasma membrane and, to a lesser extent, the organic cation transporter 3 (Yoshikawa et al., 2013). Histamine Receptors. The differing potency of antago- nists in blocking histamine action to increase the contraction rate in isolated mouse atria and gastric acid secretion or to induce smooth muscle contraction in isolated guinea pig led to the first classification of histamine receptors into the H1 Fig. 1. The histaminergic system in the rat brain. Histamine-synthesizing and H2 subtypes by Ash and Schild (1966), supported by the neurons are located in the tuberomamillary nucleus, and these neurons send projections to the CNS through three major pathways, subsequent development of selective H2 receptor (H2R) an- two ascending bundles that innervate the forebrain structures, and one tagonists (Parsons and Ganellin, 2006). The bovine H1 re- descending bundle reaching the spinal cord. Thal, thalamus; Str, . ceptor (H1R) and the canine H2R were cloned in 1991 (Gantz et al., 1991; Yamashita et al., 1991), allowing for the classifi- cation of these receptors into the class A, -like, of 2 current, active even at 70 mV, appears responsible for G protein-coupled receptors (GPCRs). H1Rs and H2Rs are Downloaded from spontaneous firing, with low-threshold depolarizing Ca21 expressed in the brain and the former signals primarily currents contributing to the repetitive firing. The action through Gaq/11 proteins, whereas the latter activates mainly 21 potential is broad with a significant contribution from Ca Gas proteins (Panula et al., 2015). currents followed by a pronounced (15–20 mV) after hyperpo- A third receptor (H3R) was pharmacologically identified by larization, which activates a depolarizing cationic current (Ih) Arrang et al. (1983) and cloned in 1999 by Lovenberg et al.; the and two A-type K1 currents that delay the return to resting H R activates Ga proteins and is expressed almost exclu-

3 i/o molpharm.aspetjournals.org potential. The Ca21 currents mediate dendritic histamine sively by neuronal cells of the CNS and the peripheral nervous release and are the target of the autoreceptor-mediated system (Panula et al., 2015). Soon after, a fourth receptor was on action potential firing (Haas and Reiner, cloned by several groups (e.g., Nakamura et al., 2000; Oda 1988; Haas et al., 2008). et al., 2000). The H4Rismainlyexpressedbycellsofthe The behavioral state–dependent activity of the histaminer- and, like the structurally related H3R, gic neurons is influenced by several neuronal, humoral, and activates Gai/o proteins (Panula et al., 2015). paracrine signals, and the activity is regulated mainly by excitatory inputs from the and The Histamine H Receptor the hypothalamus and by inhibitory GABAergic afferents from 3 the hypothalamic ventrolateral preoptic nucleus (Ericson In 1983 Arrang et al. reported that in rat cerebro-cortical at ASPET Journals on October 1, 2021 et al., 1991; Haas et al., 2008; Panula et al., 2015). slices labeled with [3H]-histidine, the depolarization-evoked, Histamine Synthesis, Release, and . His- Ca21-dependent release of [3H]-histamine was reduced by tamine is synthesized from the (aa) L-histidine by exogenous histamine (IC50 41 nM, maximal inhibition 61%). the enzyme HDC, which is expressed in both the neuronal The effect was insensitive to tetrodotoxin, which prevents the bodies and terminals, and the of the precursor generation and propagation of action potentials, mimicked by is the rate-limiting factor. Histamine is stored in vesicles in Na-methylhistamine, and antagonized by and neuronal cell bodies and varicosities by the vesicular with potencies significantly different from those monoamine transporter 2, VMAT-2 (Merickel and Edwards, reported for H2R blockade. More potent H2R antagonists and 1995) and is released by exocytosis upon the arrival of action selective H1R antagonists also showed low potencies. It was potentials (Haas et al., 2008). The synthesis and release of therefore proposed that autoinhibition of histamine release histamine are regulated by H3 (Arrang et al., was mediated by a novel class of receptor (H3R). In a later 1983, 1987b; Morisset et al., 2000). study (Arrang et al., 1985a), autoinhibition of depolarization- Most histaminergic fibers do not make typical synaptic evoked [3H]-histamine release was also shown for isolat- contacts (Takagi et al., 1986), and the amine is released from ed nerve terminals (synaptosomes) from rat cerebral cortex several points along the fibers, allowing its action on a large (230%) and slices of striatum (249%), (247%) number of cells. In the brain, histamine is also produced by and hypothalamus (264%). The same group reported that mast cells, which contribute modestly to the total amine levels histamine also inhibited its own synthesis evoked by de- in the adult brain, but during early postnatal development polarization in rat cerebrocortical slices (IC50 340 nM, maxi- represent the principal source of the amine (Molina-Hernández mal inhibition 70%; Arrang et al., 1987b). This effect was et al., 2012; Panula et al., 2015). competitively antagonized by burimamide and impromidine Inactivation of histamine in the brain is due primarily with potencies similar to those observed for the autoinhibition to the action of histamine-N-methyltransferase producing of release (Arrang et al., 1983), supporting the function of the telemethylhistamine that is transformed to telemethyl- H3R as an autoreceptor. imidazolacetic acid by B. In 1999, Lovenberg et al. identified a partial clone (GPCR97) is the main histamine-metabolizing enzyme in the peripheral and used it to probe a human thalamus cDNA library. This tissues, but its activity in the brain is considerably lower resulted in the isolation of a full-length clone encoding a under basal conditions (Barnes and Hough, 2002; Maldonado 445–amino-acid protein with the characteristics of class A and Maeyama, 2015). In contrast to most other aminergic GPCRs and with 20%–27% homology to recep- neuronal cells, histaminergic neurons lack a specific tors and 22% and 21.4% homology to the human H1Rand Histamine H3 Receptor 651 Downloaded from molpharm.aspetjournals.org at ASPET Journals on October 1, 2021

Fig. 2. Alignment of the amino acid sequence of the human, monkey, guinea pig, rat, and mouse H3Rs. Sequences were obtained from Uniprot (Washington, DC) and correspond to the full-length H3R (445 aa). Alignment was performed with the Clustal Omega server from the European Bioinformatic Institute (Cambridge, UK). The highly conserved sequences in the seven transmembrane domains are shown in gray. The DRF and NPVLY motifs and the glycosylation site (Asn11) are well conserved among species (green). Residues in blue are responsible for the interspecies differences in H3R pharmacology. Residues in red are likely to be involved in the receptor high constitutive activity on the basis of their identity with a mutated b2- adrenoceptor. The third intracellular loop (ICL3) possesses a region (residues 236–300; italics) that is highly variable among species, followed by a highly conserved sequence. The hH3Rhas$93% sequence identity with the other species, and the same identity can be found in guinea pig, mouse, and rat sequences, with 99% identity between mouse and rat, and among the primate proteins. *, conserved residues; :, conservative ; •, nonconservative mutations. 652 Nieto-Alamilla et al.

H2R, respectively. Upon transfection into human embryonic common seven-transmembrane (TM) domain structure that cell line HEK-293, rat C6 glioma cells, and human SK-N-MC forms the core, an extracellular amino terminus (NT), an neuroblastoma cells, GPCR97 displayed a pharmacologic intracellular carboxyl terminus (CT), three extracellular profile practically indistinguishable from that of the native (ECL), and three intracellular (ICL) loops. H3R. Soon after, the receptor was cloned by sequence similar- The H3R possesses a DRF motif in the interface of TM3 and ity from various other species, namely, rat, guinea pig, mouse, ICL2 (instead of the DRY sequence common to most class A and monkey, with a high level of homology ($93%) across GPCRs), a NPVLY motif in TM7 (corresponding to the NPXXY these species (see Fig. 2). motif present in all GPCRs), and a palmitoylation site in the CT (Cys428) that allows for the formation of helix 8 (Fig. 3). A Expression in the CNS disulfide bond is formed by Cys107 and Cys188 on ECL1 and ECL2, respectively. The H R has a short NT (39 aa), with a The H R is expressed mainly by neurons and in very low 3 3 glycosylation site on Asn11, and a long ICL3 (142 aa). These density by glial cells (Arrang et al., 1987a; Ferreira et al., segments are the loci of the naturally occurring mutations 2012). The distribution of the H R in the CNS has been studied 3 D19E and A280V, respectively (Wiedemann et al., 2002), and via in situ hybridization (mRNA), reverse transcription poly- cleavage through splicing of the ICL3 leads to several H R merase chain reaction (RT-PCR) (mRNA), and autoradiogra- 3 isoforms as discussed below. phy (binding sites) in rodents, humans, and monkeys. In situ

Since 2000, the rat, guinea pig, monkey, and mouse Downloaded from hybridization studies report very high levels of H R mRNA in 3 encoding the H R have been cloned (Lovenberg et al., 2000; the cortex (mainly in the V layer, with lower expression in 3 Tardivel-Lacombe et al., 2000; Chen et al., 2003; Yao et al., the superficial layers), hippocampus (CA1 and ventral CA3 2003), and this work revealed a homology of $93% in the H R pyramidal layers of Ammon’s horn), caudate, and . 3 protein sequence among these species (Fig. 2). The interspe- Strong mRNA expression is also observed in the anterior cies differences in the pharmacologic profiles rely on a double olfactory nucleus, amygdala, bed nucleus of the stria termi- change in residues 119 and 122 located near Asp114 in TM3. nalis, , thalamus (mostly in the sensory and intra- molpharm.aspetjournals.org Human and monkey receptors have Thr119 and Ala122 at laminar nuclei), and some hypothalamic nuclei, particularly these species-variant sites, whereas rodents have Ala119 and the TMN, where histaminergic neurons are located. Low to Val122, with the exception of the guinea-pig receptor (Thr119 moderate mRNA expression is detected in the habenula and and Val122). Compared with the human H R (hH R), a single- zona incerta; the signals are very low in the globus pallidus, 3 3 residue change (V362I) in TM6 is found in the rat, mouse, and substantia nigra (SN), and substantia innominata and are not guinea pig. No differences exist between human and monkey detected in the (Tardivel-Lacombe et al., H Rs in the transmembrane domains (Hancock et al., 2003). 2000; Pillot et al., 2002; Sallmen et al., 2003). 3 In contrast to the small changes in the helical domains, a Analysis by RT-PCR of the expression of the H R isoforms of 3 significant number of differences among species are found in a

445 and 365 aa in the (see description of the at ASPET Journals on October 1, 2021 65–66 aa-length sequence in the ICL3 (aa 236–300 in the receptor isoforms later herein) indicates high levels in cere- hH R), but this does not affect the presumed Ser and Thr bellum and caudate; moderate in the hypothalamus and 3 substrates of phosphorylation, suggesting a conserved kinase thalamus; low expression in the SN, hippocampus, prefrontal modulation profile. cortex, corpus callosum, and amygdala; and very low levels in the spinal cord (Bongers et al., 2007b). Binding studies show a similar H3R distribution in primate Determinants of G Protein–Coupling and Activation and rodent . The receptor is widely expressed but with Structurally and functionally, two faces can be identified on heterogeneous density, and high levels are found in cerebral all GPCRs: the extracellularly accessible orthosteric binding cortex (except in layer V), tenia tecta, , site and the internal region responsible for G-protein activa- striatum, hippocampus, bed nucleus of the stria terminalis, tion. The crystallization of GPCRs coupled to a G protein has olfactory nuclei, some hypothalamic nuclei (mainly the TMN), provided insight into the mechanisms of receptor-G protein amygdala, and pyriform cortex. In contrast to mRNA expres- interaction and activation of the latter. These studies show sion, dense binding is found in the globus pallidus and the that the a-CT and the helixes 4 and 5 of the Ga subunit dock to substantia nigra pars reticulata (SNr). A low density of a cavity formed mainly by TM5, TM6, and ICL2 in the GPCR, binding sites is found in locus coeruleus and raphe nuclei, which adopts an “open” conformation upon receptor activa- and the cerebellum and the are scarcely tion. The Arg of the DRY motif plays a key role in docking the labeled (Martinez-Mir et al., 1990; Pollard et al., 1993; a-CT of the G protein (Rasmussen et al., 2011) and residues in Anichtchik et al., 2000; Pillot et al., 2002). ICL3, helix 8, and the CT appear to contribute to stabilizing The H R location is mainly presynaptic, either as autor- 3 the receptor-G protein interaction because a truncation close eceptor or as heteroreceptor, but there is also evidence for a to the NPXXY motif prevents G protein activation (van Rijn postsynaptic location of the H R in striatum, cerebral cortex, 3 et al., 2013; Flock et al., 2015). hippocampus, nucleus accumbens, lateral hypothalamus and Computational models of the H R-G protein interaction zona incerta (Pillot et al., 2002; González-Sepúlveda et al., 3 have not yet been published, but functional studies suggest 2013; Parks et al., 2014). that ICL3 plays a role in G-protein activation. Alternative splicing generates several H3R isoforms (see later), and the Structure hH3R of 445 aa (hH3R445) inhibited forskolin-induced cAMP With more than 800 genes encoding GPCRs, these pro- formation in Chinese hamster ovary (CHO) cells, but the teins constitute the largest family of membrane proteins hH3R365 (lacking 80 aa in ICL3) failed to do so (Cogé et al., contained in the . These receptors share a 2001). In rat C6 glioma cells, the hH3R365 was less efficacious Histamine H3 Receptor 653

Fig. 3. Structure of the human H3R. As a GPCR, the H3R contains seven spanning transmembrane domains, an extracellular amino terminus (NT), an intracellular car- boxyl terminus (CT), three extracellular (ECL), and three intracellular (ICL) loops, with a long ICL3 (142 aa). Poten- tial residues for phosphorylation are shown in green. The conserved DRF and NPVLY motifs are shown in yellow. The naturally occurring mutations D18E and A280V are depicted in blue. The glycosylation site (Asn11) is shown in red, the palmitoylation site (C228) in gray. Residues Thr119 and Ala122 (purple) are responsible for the in- terspecies pharmacologic differences. Residues indicated in black in ECL1 and ECL2 correspond to the cysteins forming a disulfide bond important for receptor trafficking. Residues important for recognition are colored in pink. Downloaded from in a mobilization assay (Esbenshade et al., 2006), expression could be detected only after stabilization with butagonistswere3-to20-foldmorepotentintheReceptor either an agonist or ; furthermore, this receptor Selection and Amplification Technology assay, based on showed increased agonist affinity and reduced efficacy b-galactosidase activity (Wellendorph et al., 2002). The rat (Alewijnse et al., 2000). There is no direct evidence for a role molpharm.aspetjournals.org H3R413 and H3R397 isoforms that lack 32 and 48 aa in ICL3 of the DRF motif in H3R constitutive activity, however. showed similar efficacy and higher agonist potency for in- As pointed by Morisset et al. (2000), the CT of ICL3 in the hibition of forskolin-induced cAMP formation, but for 42/44- rat H3R has a stretch of 8 aa that is similar (six identical and mitogen-activated protein kinase (MAPK) phosphorylation, two conserved residues) to the corresponding sequence of a the H3R445 coupled considerably better (Drutel et al., 2001). mutated human b2-adrenoceptor with high constitutive activ- The naturally occurring A280V on ICL3 also ity (Lefkowitz et al., 1993). This region is critical for constitu- modifies the functionality of the hH3R445 to inhibit cAMP tive activity in other native or mutated GPCRs. Although the accumulation and stimulate 42/44-MAPK phosphorylation sequence is conserved in all H3R isoforms and species (see Fig. (Flores-Clemente et al., 2013). 2), constitutive activity varies among isoforms and can differ

Altogether, the previous information indicated that there is between species and cell lines (Arrang et al., 2007). at ASPET Journals on October 1, 2021 not a single structural determinant for the H3R functionality but that the interplay of several regions provides the appro- H3R Isoforms priate physiologic output. The existence of H3R isoforms was initially suggested by the pharmacologic heterogeneity of the receptor expressed in Constitutive Activity and Determinants several brain regions in binding and functional assays (West The term constitutive activity refers to a -independent et al., 1990). The molecular cloning of the receptor indicated state of the receptor that spontaneously adopts the active that the structure of the hH3R comprised three exons and conformation. The H3R possesses high constitutive activity as two introns (Tardivel-Lacombe et al., 2001; Wiedemann et al., indicated by the reduction of basal G-protein activation induced 2002) or four exons and three introns (Cogé et al., 2001), which by inverse agonists (Wieland et al., 2001; Rouleau et al., 2002). allows for the generation of isoforms via RNA splicing. Constitutive activity has been shown mainly for transfected Alternatively, for humans and rodents, the last intron is human and rat H3Rs but also for native rodent receptors with proposed to be a pseudointron located in the region coding 35 inverse agonists reducing basal [ S]-GTPgS binding to mem- for ICL3, which is retained in the hH3R445 but deleted in the branes from the cerebral cortex and hippocampus, enhancing hH3R413 (Tardivel-Lacombe et al., 2001; Bongers et al., depolarization-induced [3H]-histamine release from cerebro- 2007a). In both proposed structures, the two first introns are cortical synaptosomes and increasing the levels of the hista- located in the same position in the human and rodent genes, mine metabolite tele-methylhistamine in homogenates from suggesting the existence of a variety of functional and the cerebral cortex (Morisset et al., 2000; Sallmen et al., 2003). nonfunctional isoforms with certain similarity among species The DRY motif is responsible for the equilibrium between the (Tardivel-Lacombe et al., 2000; Drutel et al., 2001; Morisset inactive and active receptor conformations and therefore plays et al., 2001; Wellendorph et al., 2002). a pivotal role in constitutive activity. A salt bridge between the RT-PCR analysis identified several isoforms that differ in Arg in the DRY motif (TM3) and an Asp or Glu in TM6 stabilizes the length of their NT or CT, deletions in the ICL3 or shorter or “locks” the inactive state. Upon receptor activation, this sequences in TMs. To date, the pharmacologic and functional interaction is broken and the Arg residue in TM3 rotates toward characteristics of the H3R isoforms have been evaluated only TM5 to form a hydrogen bond with a Tyr residue to establish an in heterologous systems (Table 1). “active lock” (Valentin-Hansen et al., 2012). Accordingly, the Some of the identified isoforms lack regions critical for R112A mutation in the hH4R prevents G-protein activation agonist binding (TM3 and 5–7) or signaling (ICL2, ICL3, and (Schneider et al., 2010), and the R116A mutation in the rat H2R CT) and therefore do not trigger the signaling pathways resulted in a highly structurally instable receptor whose typically associated with H3R activation (Wess, 1997; Uveges 654 Nieto-Alamilla et al. et al., 2002; Oldham and Hamm, 2007; Ishikawa et al., 2010; PC12 cells (Morrey et al., 2008), support- Kim et al., 2011; Kuramasu et al., 2011); however, three rat ing the participation of Gbg dimers in these processes. isoforms (rH3R497,rH3R465, and rH3R449) that do not possess Activation of G Protein–Gated Inwardly Rectifying 1 TM7, but do have an extracellular CT of 105 aa without K Channels. Gbg subunits bind and activate G protein– homology to the functional isoforms, reduce the cell surface gated inwardly rectifying K1 channels (GIRK) (Bünemann expression of the rat H3R445 upon coexpression in COS-7 cells et al., 2001) and transfected hH3R445 and hH3R365 activate (Bakker et al., 2006). The expression and signaling of functional channels formed by the GIRK1 (Kir3.1) and GIRK4 (Kir3.4) H3Rs could thus be regulated by isoforms incapable of trigger- subunits expressed in Xenopus oocytes (Sahlholm et al., 2012). ing the signaling pathways described to follow. These isoforms GIRKs can inhibit synaptic transmission (Meneses et al., 2015), could also directly interact with other GPCRs and affect their and activation of presynaptic GIRKs would thus represent an binding or signaling properties. Furthermore, noncanonical additional mechanism for H3Rs to modulate neurotransmitter signaling, either agonist-independent or mediated by alterna- release. Activation of GIRK channels by H3Rs has also been tive pathways, cannot be discarded for the truncated or longer observed at the postsynaptic level in neurons producing H3R isoforms and merits further investigation. melanin-concentrating hormone (MCH), where the effect was prevented by GDPbS, an inhibitor of G-protein signaling (Parks et al., 2014). Signaling Pathways

Phospholipase C Activation. In transfected CHO and Downloaded from The coupling of the H3RtoGai/o proteins was first suggested SK-N-MC cells, activation of the hH3R445 induces a significant 21 21 by the inhibitory effect of pertussis toxin (PTX) activity, which increase in the intracellular concentration of Ca ions ([Ca ]i) 3 decreased the affinity for [ H]-NMHA of the H3R endoge- as a result of phospholipase C (PLC) activation and release of nously expressed by murine pituitary AtT cells (Clark et al., Ca21 from intracellular stores via inositol-1,4,5-trisphosphate 35 1993) and prevented H3R-stimulated [ S]-GTPgS binding in (IP3) formation (Cogé et al., 2001; Bongers, 2008). The H3R- rat cerebrocortical membranes (Clark and Hill, 1996). As for 21

mediated increase in [Ca ]i was prevented by PTX, which molpharm.aspetjournals.org other GPCRs, both the Ga subunits and the Gbg complexes implicates the participation of Gai/o proteins (Bongers, 2008). 21 mediate the Gai/o protein-dependent signaling of the H3R (Fig. 4). The PLC/IP3/Ca pathway is most often triggered by the Ga Inhibition of Adenylyl Cyclases. In the study that subunits of Gaq/11 proteins, but Gbg complexes can also activate reported the cloning of the hH3R (Lovenberg et al., 1999), PLCb by binding to a region (PH and Y domains) different from receptor activation inhibited forskolin-induced cAMP accumu- the Gaq/11 subunit binding domain (C2 domain and carboxyl lation, and this effect was disrupted by PTX (Shi et al., terminal region; Rebecchi and Pentyala, 2000; Rhee, 2001). 2012). Likewise, for other Gai/o protein-coupled GPCRs, a direct Activation of the MAPK Pathway. H3R activation interaction between the Gai/o subunit and sensitive adenylyl stimulates 42/44-MAPK phosphorylation both in heterologous cyclases (1, 3, 5, 6, and 8) appears to be the mechanism that systems and native tissues (Drutel et al., 2001; Giovannini mediates this effect (Cooper and Crossthwaite, 2006). et al., 2003; Flores-Clemente et al., 2013). G complexes at ASPET Journals on October 1, 2021 1 1 bg Inhibition of the Na /H Exchanger. The activity of appear to play a central role in this action because pharma- 1 1 the Na /H exchanger (NHE) represents one of the key cologic inhibition and Ga-transducin, a Gbg scavenger, pre- mechanisms for restoring the intracellular pH after vent H3R-mediated 42/44-MAPK phosphorylation (Lai et al., -induced acidosis by extruding protons concomitantly 2016). Other mechanisms, however, such as the binding to 1 1 with Na influx (Karmazyn, 1999). A rise in intracellular Na activated receptors of b-arrestins, that act as a signaling 1 - may reverse the Na /Cl -dependent noradrenaline trans- scaffold (Gutkind, 2000) or the transactivation of the epider- porter and induce carrier-mediated neurotransmitter release. mal growth factor receptor (Lai et al., 2016) could also H3R activation reduces NHE activity in sympathetic nerve contribute to MAPK activation. terminals, leading to inhibition of noradrenaline release in Activation of the Phosphatidylinositol 3-Kinase myocardial ischemia (Silver et al., 2001); the mechanism is not (PI3K) Pathway. In transfected cells, primary cultures of fully understood, although a direct Gai/o subunit/NHE in- rat cerebrocortical neurons, and rat striatal slices, H3R teraction appears likely (van Willigen et al., 2000). activation stimulates the phosphorylation of Akt or protein 21 Inhibition of N- and P/Q-Type Voltage-Gated Ca kinase B, which subsequently phosphorylates and thereby Channels. The inhibitory effect of H3Rs on neurotransmitter inhibits the action of synthase kinase 3-b (GSK3b) release (see later discussion) is most likely linked to the (Bongers et al., 2007c). This action on the PI3K/Akt pathway 21 reduction in depolarization-induced Ca entry via the binding was prevented by PTX and probably depends on Gbg com- of Gbg complexes to the pore-forming a1-subunit of N- and P/Q- plexes, which are known to activate PI3K (Murga et al., 1998). 21 type voltage-gated Ca channels (Zamponi and Currie, 2013). Stimulation of Phospholipase A2. The activation of Accordingly, H3R activation reduces depolarization-induced phospholipase A2 by the H3R induces the release of arachi- 21 Ca entry in dissociated hypothalamic histaminergic neu- donic acid, docosahexaenoic acid, and lysophospholipids, rons (Takeshita et al., 1998), striatal synaptosomes (Molina- inducing functional consequences such as the relaxation Hernández et al., 2001), transfected human neuroblastoma of guinea pig by enhanced release of the SH-SY-5Y cells (Silver et al., 2002), and transfected rat -derived relaxing factor, a metabolite of arachi- pheochromocytoma PC12 cells (Morrey et al., 2008). The donic acid (Burgaud and Oudart, 1993). 21 inhibition of voltage-gated Ca currents by H3Rs in histamin- ergic neurons was abolished by PTX (Takeshita et al., 1998), Regulation of H3R Signaling and both a Gbg scavenger and a phosphoducin-like anti-Gbg peptidepreventedtheH3R-mediated reduction in depolarization- Desensitization. This process, which leads to changes in induced Ca21 entry and neurotransmitter exocytosis in signaling efficacy and receptor expression at cell surfaces, Histamine H3 Receptor 655

TABLE 1

Brain expression and signaling of H3R isoforms from different species

The human H3R329a and H3R329b isoforms possess the same number of amino acids but differ in the region where alternative splicing occurs.

Isoform Species (aa) Expression in the Central Nervous System Signaling References

2+ Human H3(445) Thalamus, striatum, cerebral cortex, cerebellum, ↓ cAMP, ↑ [Ca ]i Lovenberg et al., 1999; Nakamura et al., 2000; Cogé amygdala, substantia nigra, hippocampus, ↑ p42/p44-MAPK, et al., 2001; Tardivel-Lacombe et al., 2001; Tsui, hypothalamus, corpus callosum, spinal cord ↑ [35S]-GTPgS 2001; Wiedemann et al., 2002; Wellendorph binding et al., 2002; Gallagher and Yates, 2007; Bongers H3(431) Amygdala, cerebellum, striatum, thalamus, ND et al., 2007a,b prefrontal cortex, striatum, 2+ H3(415) Thalamus, cerebellum, amygdala ↑ [Ca ]i 2+ H3(365) Cerebellum, thalamus, hypothalamus, striatum, ↑ [Ca ]i, substantia nigra, hippocampus, amygdala, ↓ cAMP, prefrontal cortex ↑ [35S]-GTPgS binding H3(329a) Substantia nigra, amygdala, cerebral cortex, NF hypothalamus H3(326) Substantia nigra, prefrontal cortex, amygdala, ND hypothalamus Downloaded from H3(413) Striatum, amygdala ND H3(453) ND ↓ cAMP H3(301) ND NF H3(373) Hippocampus, substantia nigra, amygdala, ↓ cAMP hypothalamus H3(309) ND NF H3(221) ND ND H3(409) ND ND molpharm.aspetjournals.org H3(329b) ND ND H3(395) ND ND H3(379) ND ND H3(293) ND ND H3(290) ND ND H3(351) ND ND H3(340) ND ND 2+ Monkey H3(445) Frontal cortex, parietal cortex, occipital cortex, ↑ [Ca ]i Yao et al., 2003; Strakhova et al., 2008 parahippocampal gyrus, hippocampus, , putamen, amygdala, thalamus, cerebellum 2+ H3(413) Frontal cortex, parietal cortex, para-hippocampal ↑ [Ca ]i gyrus, caudate nucleus, putamen, amygdala, at ASPET Journals on October 1, 2021 thalamus 2+ H3(410) Frontal cortex, parietal cortex, parahippocampal ↑ [Ca ]i gyrus, caudate nucleus, putamen, amygdala, thalamus H3(335) Frontal cortex, parietal cortex, occipital cortex, NF parahippocampal gyrus, Hippocampus, caudate nucleus, putamen, amygdala, thalamus, cerebellum Rat H3(445) Cerebral cortex, hippocampus, midbrain, ↓ cAMP, Lovenberg et al., 2000; Drutel et al., 2001; Morisset hypothalamus, striatum, brainstem, cerebellum, ↑ p42/p44-MAPK et al., 2001; Bakker et al., 2006; Gbahou et al., olfactory tuberculum, spinal cord 2012 H3(413) Cerebral cortex, hippocampus, midbrain, striatum ↓ cAMP, ↑ p42 /p44-MAPK ↑ [3H]AA release ↑ [35S]-GTPgS binding H3(410) Cerebral cortex, hippocampus, midbrain, striatum ND H3(397) Cerebral cortex, hippocampus, midbrain, ↓ cAMP, hypothalamus, striatum, olfactory tuberculum ↑ p42/p44-MAPK H3(497) Cortex layers II–VIb, caudate-putamen, piriform NF cortex, hippocampus H3(465) Cortex layers II–VIb, caudate-putamen, piriform NF cortex, hippocampus H3(449) Cortex layers II–VIb, caudate-putamen, piriform NF cortex, hippocampus 2+ Mouse H3(445) Cerebral cortex, striatum, hypothalamus ↑ [Ca ]i Chen et al., 2003; Rouleau et al., 2002 H3(413) Cerebral cortex, striatum, hypothalamus ND H3(397) Cerebral cortex, striatum, hypothalamus ND Guinea pig H3(445) Cerebral cortex, striatum ND Tardivel-Lacombe et al., 2000 H3(415) Cerebral cortex, striatum ND Dog H3(ND) ND ND Ireland-Denny et al., 2001

2+ 2+ ↑, increase; ↓, decrease; AA, arachidonic acid; [Ca ]i, intracellular Ca concentration; ND, not determined; NF, nonfunctional. 656 Nieto-Alamilla et al.

Table 2) and efficacy (Emax) and potency (pEC50,EC50,pKB, 35 pA2,pD2) through the analysis of [ S]-GTPgS binding, cAMP formation, 42/44-MAPK phosphorylation, calcium mobiliza- tion, and PI3K activation (Table 3). In 2008, the crystal structure of the GPCR was resolved (Scheerer et al., 2008), leading to a revolutionary change in the study of GPCR-drug interactions. Although the crystal structure of the H3R has yet to be elucidated, homology models and point-mutation studies allow for the assessment of ligand recognition by its binding pocket.

Determinants of Histamine Binding Histamine (2-[4-imidazolyl]ethylamine) is a hydrophilic nonchiral molecule consisting of an ring and an ethylamine side chain, and its binding to the H3R depends on features shared by other biogenic amine receptors. Although the ligand binding site comprises residues in TM3–TM7, two Downloaded from Fig. 4. H R signaling pathways. H R activation triggers or modulates 3 3 main residues are essential for histamine binding. One is the several pathways through the Ga subunits and Gbg complexes of Gai/o proteins. AA, arachidonic acid; AC, adenylyl cyclases; cAMP, 39,59-cyclic negatively charged Asp114 in TM3 that interacts with the ; MAPK, mitogen-activated protein kinases; protonated amine group of histamine, and the other is Glu206 NHE, Na+/H+ exchanger; PI3K, phosphatidylinositol 3-kinase; PKA, pro- in TM5, which forms a hydrogen bond with the nitrogen tein kinase A; PLA2, phosholipase A2; PLC, phosholipase C. present in the imidazole ring.

In addition to Glu206, other residues important for histamine molpharm.aspetjournals.org binding are Trp196, Thr201, Ala202, Thr204, and Phe208 in represents a major mechanism to regulate GPCR functional TM5. Mutations in these residues decrease binding affinity, responses. Homologous desensitization is triggered by the with the E206A mutation resulting in the most marked change. phosphorylation of activated receptors by GPCR kinases, Interestingly, variations in binding affinity induced by muta- whereas in the heterologous process, activation of one GPCR tions are not always matched in functional assays, with the leads to the desensitization of one or more unrelated receptors W196A, T204A, E206A, and F208A mutations increasing in the same cell. The latter process often involves GPCR ligand potency to inhibit cAMP formation, indicating that phosphorylation by second messenger–activated kinases, in conformational changes in the binding pocket do not necessarily particular, protein kinases A (PKA) and C (PKC). GPCR

translate into receptor-driven G-protein activation (Uveges at ASPET Journals on October 1, 2021 phosphorylation results in conformational changes that im- et al., 2002). Other residues involved in histamine binding are pair G-protein activation and triggers receptor internalization Tyr115 and Cys118 in TM3; Trp371, Tyr374, and Leu401in (Gainetdinov et al., 2004; Gurevich et al., 2012). TM6; and Tyr189 in ECL2 and Trp402 in TM7 (Ishikawa et al., In CHO-K1 cells stably transfected with the hH R , 3 445 2010). The high affinity of the H R for the exposure to agonists results in functional desensitization, as 3 does not rely on Asp114 (conserved in all four histamine well as reduced receptor expression in the cell surface owing to receptors and essential for histamine binding) but on Glu206, the action of GPCR kinases 2/3 and clathrin-dependent endo- only present in H Rs and H Rs, explaining the nonselective cytosis (Osorio-Espinoza et al., 2014). In the same expression 3 4 actions of several classic H R ligands at the H R (Axe et al., system, the hH R also experiences PKC-mediated heterolo- 3 4 3 445 2006). The increased affinity of H Rs and H Rs for histamine gous desensitization upon activation of a second GPCR coupled 3 4 may be due, at least in part, to the stronger interaction of the to the PLC/IP /DAG pathway (Montejo-López et al., 2016). 3 imidazole ring with Glu206 compared with the interaction with RGS Proteins. The regulator of G-protein signaling (RGS) the Asn or Thr residue found on the same position in H Rs or proteins modulates the intracellular effects of activated 1 H Rs, respectively (Uveges et al., 2002). GPCRs. Four RGS subfamilies (RZ, R4, R7, R12) act as 2 The previous information allows a pharmacophore struc- GTPase-activating proteins to increase the rate of GTP ture to be drawn for the H R (Fig. 5), where Glu206 anchors hydrolysis by Ga subunits (Hollinger and Hepler, 2002; 3 the imidazole moiety of histamine and the other residues form Sjögren et al., 2010). Whereas there are no reports on the a lipophilic bed in which histamine lays, favoring the in- regulation by RGS of the H R signaling, RGS proteins are 3 teraction of the basic amine moiety with Asp114 in TM3 (de coexpressed with H Rs in the CNS, for example, in cerebral 3 Esch et al., 2000). cortex (RGS 4–8, 10), nucleus accumbens and striatum (RGS 4, 8, 9), hippocampus (RGS 7, 8, 10), and hypothalamus (RGS 4, 6, 7, 8) (Gold et al., 1997), making the RGS-mediated Binding of Synthetic Imidazole-Containing and Non-imidazole Ligands regulation of H3R signaling an aspect deserving attention. Imidazole-Containing Agonists. So far, all agonists at Pharmacology the H3R are based on the structure of histamine and therefore contain the imidazole moiety, which is critical for agonist The H3R shows a complex pharmacology, with acting activity (Leurs et al., 1995). Modifications of the imidazole ring as full agonists, partial agonists, neutral antagonists, inverse have been unsuccessful. By contrast, modifications of the agonists, and protean ligands. H3R affinity for ligands has histamine side chain that preserve the basic amino group or been determined by radioligand binding assays (Ki or pKi, other proton donor moieties have allowed for the design of Histamine H3 Receptor 657

TABLE 2

Affinities of the H3R for agonists and antagonists

Data reported as Ki were converted to pKi. For recombinant receptors all values refer to the H3R of 445 aa.

pKi

Rat Mouse Guinea Pig Monkey Dog Human Imidazole- Containing Agonists Histamine Native 8.27a 7.92 6 0.54 (high)b 7.58a 7.88c 8.50 6 0.08d 8.59 6 0.08d 8.28e 6.09 6 0.61 (low)b 8.18 6 0.15d 8.63f 7.92g 8.08c d 8.29 6 0.03 8.20 6 0.10e 8.30 f 8.13i 7.82 j Recombinant 7.87g 8.78 6 0.10k 7.81g 8.57f 8.58f Downloaded from 7.69l 7.88l 5.70 6 0.15m 8.20 6 0.04n 7.89 6 0.07n 8.55 6 0.01k 8.00 6 0.10o 8.03 6 0.06p 8.30 6 0.10q 8.60 6 0.00r 8.50s molpharm.aspetjournals.org 8.40 6 0.20t RAMH Native 8.88a,e 7.91 6 0.09 (high)b 8.49a 8.50c 8.93 6 0.19d 9.15 6 0.06d 8.82g 6.67 6 0.21 (low)b 8.63 6 0.25d 8.82c 8.71 6 0.08d 9.48 6 0.16u 9.16 6 0.07v 8.95i 10.07 6 0.16u 8.71 6 0.08v

Recombinant 8.72g 8.40 j 9.55 6 0.04k 8.67g 8.44l 8.56l 6.40 6 0.20m 8.91 6 0.07n at ASPET Journals on October 1, 2021 8.62 6 0.07n 9.41 6 0.05k 9.35 6 0.20v 8.20 6 0.10o 8.36 6 0.07p 8.92 6 0.11q 9.00 6 0.10r 9.16 6 0.08v 8.56w SAMH Native 7.30a 5.93 6 0.04b 7.30a 7.69c 7.79 6 0.11d 7.49c 7.33 6 0.06d 7.63 6 0.18d 8.33 6 0.18d 7.11i

Recombinant 7.20 6 0.10o 7.60 6 0.20r NAMH Native 8.92g 8.67 6 0.27d 8.76c 9.15 6 0.09d 9.41 6 0.06d 8.78 6 0.13d 9.99 6 0.24u 9.08c 9.15i 10.31 6 0.24u

Recombinant 8.61g 8.82g 9.22 6 0.03n 8.70 6 0.09n 8.95 j 8.40 6 0.10o 9.00 6 0.10r 9.80s Native 9.30 g 9.50 6 0.66 (high)b 8.68 6 0.34d 9.25 6 0.06d 9.58 6 0.06d 8.99 6 0.20d 7.48 6 0.33 (low)b

Recombinant 8.85g 9.79 j 8.79 g 7.50 6 0.08m 9.30 6 0.10o 9.32 6 0.04p 9.51 6 0.03q 9.40 6 0.10r 9.70s 9.40 6 0.10t 9.30x (continued) 658 Nieto-Alamilla et al.

TABLE 2—Continued

pKi

Rat Mouse Guinea Pig Monkey Dog Human Native 10.00e 9.09 6 0.18 (high)b 8.99 6 0.25d 9.01c 9.31 6 0.06d 9.67 6 0.06d 10.00 g 7.02 6 0.60 (low)b 9.50c 9.46 6 0.10d 9.79 6 0.07v 9.82i 9.53 6 0.09v

Recombinant 9.69 j 9.69 g 9.84 6 0.03k 9.22g 9.38 6 0.08n 9.20 6 0.05n 10.11 6 0.10v 9.59 6 0.09k 8.80 6 0.10o 9.23 6 0.19q 9.40 6 0.10r 9.70s 9.59 6 0.09v Recombinant Downloaded from 6.90 6 0.06m 8.84 6 0.06n 10.11 6 0.05n 8.30 6 0.10o 8.29 6 0.14p 8.50 6 0.10r Proxyfan Native 8.51 6 0.05v 8.32 6 0.13u 8.38 6 0.13v 8.80 6 0.23u Recombinant molpharm.aspetjournals.org 8.53l 8.56l 8.08 6 0.10n 7.90 6 0.10o 8.62 6 0.10v 8.35 6 0.06v 8.40 6 0.20r 7.87 6 0.07n VUF 5296 Native 7.60 6 0.10h

Recombinant 7.17 6 0.09 p VUF 5297 Native 8.76 6 0.10e at ASPET Journals on October 1, 2021

Recombinant 8.03 6 0.08 p Recombinant 9.00 6 0.10o 9.00 6 0.10x Imidazole- pKi Containing Antagonists Native 8.67a 8.37 6 0.12b 8.69a 6.61c 8.17 6 0.15d 7.13 6 0.06d 7.99 g 8.30 6 0.15y 8.34 6 0.12d 7.91 6 0.10 y 7.21f 8.10 6 0.06d 8.69 6 0.05u 8.17 6 0.12aa 6.69c 8.12f 9.08 6 0.13u 7.18 6 0.01aa 8.39i 8.34 6 0.11aa 8.85z 8.48 6 0.01y 8.15 6 0.06aa

Recombinant 8.37g 8.49 6 0.05y 7.19 6 0.03k 7.23g 8.49 f 7.13f 8.18l 7.22l 7.20 6 0.08m 7.34 6 0.04n 7.94 6 0.04n 7.24 6 0.06k 8.62 6 0.06 y 7.30 6 0.10o 8.44 6 0.07aa 7.34 6 0.13q 8.40 6 0.20bb 7.70 6 0.20r 8.44 6 0.07cc 7.70s 6.90 6 0.10t 7.85w 7.12 6 0.10y 7.14 6 0.06aa 7.40 6 0.33bb 7.14 6 0.06cc (continued) Histamine H3 Receptor 659 TABLE 2—Continued

pKi

Rat Mouse Guinea Pig Monkey Dog Human Native 9.15 6 0.05d 9.10 6 0.16y 8.70 6 0.08d 8.20 6 0.08d 6.99 6 0.08d 9.18 f 8.76 6 0.07dd 7.46 6 0.10 y 7.04f 9.22 6 0.05v 8.24 6 0.06dd 7.05 6 0.07v 8.91 6 0.04y 6.72 6 0.14y 9.20 6 0.04dd 7.05 6 0.06dd

Recombinant 9.36 f 9.08 6 0.08y 7.18 6 0.05k 7.20 f 8.40l 7.33l 8.87 6 0.08n 7.03 6 0.12n 9.38 6 0.07v 7.20 6 0.04k 9.29 6 0.05y 7.17 6 0.04q 9.29 6 0.09cc 7.40 6 0.10r 9.29 6 0.09dd 7.20 6 0.04v 7.02w 6.96 6 0.06y cc

7.20 6 0.05 Downloaded from 7.20 6 0.05dd Iodoproxyfan Native 9.69i 8.86 6 0.16b 9.76 6 0.23u 10.00 6 0.09u

Recombinant 9.20 6 0.10o

Clobenpropit Native molpharm.aspetjournals.org 9.30 g 9.28 6 0.16b 9.65 6 0.22d 8.65c 10.09 6 0.13d 9.08 6 0.13d 9.38 6 0.08d 9.57 6 0.09y 9.65 6 0.20aa 9.84 6 0.12y 8.24c 9.31i 10.09 6 0.11aa 9.11 6 0.11v 9.45 6 0.08v 9.11 6 0.11y 9.53 6 0.11y 9.11 6 0.12aa 9.45 6 0.08aa

Recombinant 9.39 g 9.50 j 9.72 6 0.10k 9.22g 8.85l 9.70 6 0.08y 8.61l 8.30 6 0.02m 9.34 6 0.06n n k 9.11 6 0.06 9.43 6 0.03 at ASPET Journals on October 1, 2021 9.82 6 0.07v 8.60 6 0.10o 9.59 6 0.09 y 8.79 6 0.08q 9.75 6 0.01aa 9.30 6 0.20r 9.30s 9.47 6 0.04v 9.23w 9.47 6 0.19 y 9.44 6 0.04aa Native 9.23 6 0.10d 9.24 6 0.21b 9.39 6 0.21d 9.59 6 0.09d 8.45 6 0.14d 10.08 6 0.11u 9.96 6 0.23u

Recombinant 8.20 6 0.10o 9.10 6 0.20r SCH 79687 Native 8.72ee 7.88ee VUF 5681 Recombinant 8.35 6 0.11p 8.90 6 0.30r Burimamide Native 8.18 6 0.15d 6.28 6 0.2b 8.27 6 0.05d 8.42 6 0.13d 8.34 6 0.21d 7.16i

Recombinant 7.90 6 0.10o Non-imidazole pKi antagonists JNJ-5207852 Recombinant 8.90 6 0.17bb 9.24 6 0.21bb (continued) 660 Nieto-Alamilla et al.

TABLE 2—Continued

pKi

Rat Mouse Guinea Pig Monkey Dog Human ABT-239 Native 7.92 6 0.11y 7.96 6 0.08y 8.59 6 0.12ff 8.61 6 0.20 y 8.34 6 0.06ff 8.49 6 0.04ff 8.41 6 0.07ff

Recombinant 8.52 6 0.08y 8.42 6 0.07y 9.51 6 0.10 y 8.87 6 0.04cc 9.35 6 0.04cc 8.91 6 0.04ff 9.35 6 0.04ff NNC 38-1049 Recombinant 8.29 gg 8.92w A-331440 Native 7.66 f 7.64f 7.73 6 0.08hh 7.63 6 0.05hh

Recombinant 8.20 f 8.71 6 0.06k 8.48f 8.23 6 0.04hh 8.45 6 0.05k Downloaded from 7.75 6 0.04q 8.00r 8.45 6 0.05hh A-349821 Native 9.12 6 0.14hh 9.37 6 0.08hh

Recombinant 8.78 6 0.12cc 9.67 6 0.14k 9.55 6 0.09k molpharm.aspetjournals.org 8.78 6 0.12hh 9.20 6 0.10r 9.39 6 0.08cc 9.39 6 0.08hh UCL1972 Native 7.41ii GSK189254 Native 8.51 6 0.11y 8.89 6 0.13 y 8.83 6 0.09y 9.59 6 0.15y

Recombinant 9.17 6 0.09 y 8.76 6 0.06 y 9.90 6 0.18y Native 7.85 jj at ASPET Journals on October 1, 2021 Recombinant 8.56 jj

SAMH, S-a-methylhistamine. aArrang et al., 1987a. eGarbarg et al., 1992. gLovenberg et al., 2000. dIreland-Denny et al., 2001. eDe Esch et al., 1999. fHancock et al., 2004a. iLigneau et al., 1994. lLigneau et al., 2000. mDrutel et al., 2001. nSchnell et al., 2010. bJansen et al., 2000. jChen et al., 2003. cWest et al., 1999. kStrakhova et al., 2008. oLim et al., 2005. pKitbunnadaj et al., 2003. qFlores-Clemente et al., 2013. rBongers et al., 2007b. sLovenberg et al., 1999. tBongers et al., 2007c. vKrueger et al., 2005. uHarper et al., 1999. wZaragoza et al., 2004. xKitbunnadaj et al., 2005. zSánchez-Lemus and Arias-Montaño, 2004. yMedhurst et al., 2007. aaEsbenshade et al., 2003. bbBarbier et al., 2004. ccCowart et al., 2005. ddEsbenshade et al., 2004. eeMcLeod et al., 2003. ffEsbenshade et al., 2005. ggMalmlöf et al., 2005. hhHancock et al., 2004b. iiGanellin et al., 1998. Histamine H3 Receptor 661

TABLE 3

Potencies of H3R agonists and antagonists For recombinant receptors all values refer to the full-length (445 aa) receptor.

pIC50 or pEC50

Drug pA2 pKB pD2 2+ PI3K/ cAMP Ca MAPK GTPgS Akt RAMH 8.50 6 0.10 (r)a 8.44 6 0.11b 7.94 6 0.17 (h)c 8.50 6 0.14 (h)c 7.60 6 0.05d 9.50 6 0.10e 7.92f 8.00 6 0.10g 8.50 6 0.10a 9.17 6 0.03h 8.22f 7.65 (r) f 8.22 6 0.35 (h)c 8.50 6 0.13i 8.02, 8.42 (h) f 8.20 6 0.10 g 8.67 (r) f 8.01 (h) f 9.47 6 0.18i 9.54 6 0.06 j SAMH 8.00 6 0.10e 6.60 6 0.10g 6.21 6 0.15d 6.80 6 0.10 g 8.31 6 0.01j Histamine 8.30 6 0.10e 7.66, 7.81, 7.30 6 0.10g 6.46 6 0.18d 7.75, 7.76k Downloaded from 8.01 6 0.03h 7.99 6 0.09b 7.40 6 0.10l 7.40 6 0.20 g 7.82 6 0.09i 8.63 6 0.10i 8.55 6 0.05 j Imetit 9.90 6 0.10e 8.13, 8.03, 8.60 6 0.10g 7.80 6 0.10d 8.40, 8.48k 9.66 (r) f 8.47 6 0.08b 8.69 (r)f 8.39 (h) f 8.14f 8.53, 8.71 (h)f molpharm.aspetjournals.org 8.92 6 0.04m 8.04f 9.79 6 0.20i 8.86 6 0.20i 9.91 6 0.05 j Immepip 9.40 6 0.10 (r)a 8.80 6 0.10g 9.40n 8.35 6 0.08d 10.40 6 0.10e 9.40 6 0.10a 9.88 6 0.02h 9.00 6 0.10 g 9.90 6 0.10n 9.90 6 0.0o 7.88q 10.30 6 0.14 j Impentamine 8.1 (r)a 7.50 6 0.10q at ASPET Journals on October 1, 2021 8.40 6 0.10e 8.10 6 0.10a 8.63 6 0.08h 9.17 6 0.11i 8.43 6 0.08 j NAMH 9.40 6 0.10e 8.03, 8.15, 7.90 6 0.10g 7.17 6 0.07d 8.50 6 0.10 g 8.34, 8.22k 9.45 6 0.05 j Methimepip 9.50 6 0.20e 9.50 6 0.20o VUF 5296 7.24 6 0.04h 6.15 6 0.08l VUF 5297 8.23 6 0.14h 6.64 6 0.06l Proxyfan 8.50 6 0.10e 7.43 6 0.06b 7.50 6 0.10g 7.83(r) f 7.61, 7.11f 7.33 (r)f 6.86 (h) f 6.20, 5.89 f 7.49, 7.68 (h)f 7.73f 7.61f 8.31 6 0.11j Thioperamide 7.50 6 0.10e 8.06 6 0.10 (r)q 7.00n 8.44 6 0.45d 6.90 6 0.10t 7.60 6 0.20 g 7.41 6 0.11 (h)q 8.44 6 0.49 (gp)r 8.13 6 0.14 (r)q 7.10 6 0.20n 6.90 6 0.10g 7.39 6 0.04 (h)q 7.88 p 7.49 6 0.34s 9.11 6 0.14 (r)q 7.41 6 0.12 (h)t 6.82 6 0.05 (h)q 8.06 6 0.10 (r)t 7.09 6 0.08 (mk)b 6.82 6 0.06 (h)t 6.10 6 0.12 (h)t 7.39 6 0.04 (h)t 6.82 6 0.06 (h)t 7.61 6 0.14 (r)t 8.13 6 0.14 (r)t 8.95v Ciproxifan 5.39, 5.30 f 6.57, 6.58 f 8.87 6 0.16 (r)q 8.12 6 0.56d 8.78 6 0.12 (r)q 7.04 6 0.17 (h)q 8.12 6 0.56s 7.03 6 0.13 (h)q 7.16 6 0.19s 9.42 6 0.11 (r)q 7.04 6 0.17 (h)s 6.86 6 0.07 (h)q (continued) 662 Nieto-Alamilla et al.

TABLE 3—Continued

pIC50 or pEC50

Drug pA2 pKB pD2 2+ PI3K/ cAMP Ca MAPK GTPgS Akt 8.87 6 0.16 (r)s 7.23 6 0.04 (mk)b 9.10 (r)f 6.59 (h)f 6.84 6 0.08t 6.59 6 0.04 (h)s 7.07 6 0.13 (h)s 6.84 6 0.08 (h)s 9.20 6 0.10 (r)s 8.78 6 0.12 (r)s Burimamide 7.00 6 0.10e 8.05 6 0.68d 7.56v 6.65 6 0.10 j Iodophenpropit 8.50 6 0.10e 9.14 6 0.61d 8.50 6 0.40 g Iodoproxyfan 10.30 6 0.10e 9.40 6 0.10e 7.41, 7.10f 8.07 6 0.66t 9.66 6 0.49d 9.80 6 0.03 (mk)b

6.79, 6.55f 9.66 6 0.49t 9.03 (r)f Downloaded from 8.35 (h)f 8.21 6 0.10 (h)t 9.04 6 0.11 (r)t 8.91 6 0.06 (h)t VUF 5681 8.41 6 0.10 j 8.08 6 0.03h A-331440 7.07 6 0.24 (r) q 7.70n 7.60 6 0.12 (r)q 7.70 6 0.08 (h) q 8.16 6 0.04 (h)q

7.38 6 0.10 (r)q molpharm.aspetjournals.org 7.60 6 0.10 g 7.37 6 0.29 (h)q 7.81 6 0.02 (mk)b A-349821 9.00 6 0.40 g 9.20 6 0.10 g 9.47 6 0.56s 9.67 6 0.05 (mk)b 9.09 6 0.08 (h)s 8.27 6 0.12u 8.57 6 0.09 (r)s 8.24 6 0.10 (h)s 9.26 6 0.02 (h)s 8.27 6 0.12r (h)s 8.08 6 0.10 (r)s 8.62 6 0.11 (r)s ABT-229 7.87 6 0.15 (r)u 7.89 6 0.04 (h)w 9.04 6 0.04 (h)w at ASPET Journals on October 1, 2021 7.87 6 0.15 (h)w 7.60 6 0.05 (r)w 8.34 6 0.14 (r)w 8.74 6 0.44 (gp)w GSK189254 8.20 6 0.12m 9.06 6 0.02m JNJ-5207852 8.94 (r)x 9.84 (h)x NCC 38-1049 8.63y Pitolisant 9.79z

Gp, guinea pig; h, human; mk, monkey; NAMH, Na-methylhistamine; r, rat. aDrutel et al., 2001. bStrakhova et al., 2008. cFlores-Clemente et al., 2013. dIreland-Denny et al., 2001. eLim et al., 2005. fKrueger et al., 2005. gBongers et al., 2007b. hKitbunnadaj et al., 2003. iUveges et al., 2002. jBaker, 2008. kChen et al., 2003. lDe Esch et al., 1999. mMedhurst et al., 2007. nBongers et al., 2007c. oKitbunnadaj et al., 2005. pSánchez-Lemus and Arias-Montaño, 2004. qHancock et al., 2004a. rLovenberg et al., 2000. sEsbenshade et al., 2004. tEsbenshade et al., 2003. uCowart et al., 2005. vHew et al., 1990. wEsbenshade et al., 2005. xBarbier et al., 2004. yMalmlöf et al., 2005. zLigneau et al., 2007. Histamine H3 Receptor 663 more selective and potent agonists. Like histamine, these Imidazole-Containing Antagonists. In addition to the molecules bind to the H3R by using Glu206 as anchor for the imidazole moiety, most of these compounds possess a central imidazole moiety and establishing hydrogen bonds with electronegative group and a cyclic moiety (Fig. 7). These Asp114 (Fig. 5). groups form a conserved pharmacophore with three interac- The first highly selective and potent H3R ligands were the tions: 1) a hydrogen bond of the imidazole ring with Glu206 in agonist RAMH (R-a-methylhistamine) and the antagonist TM5; 2) a salt bridge of the central electro-negative group with thioperamide, and the differences in the affinity and potency either Tyr374 in TM6 or Asp114 in TM3, which may dictate of the ligand enantiomers demonstrated the stereoselectivity the torsion of the antagonist; and 3) a p-stacking of the of the H3R (Arrang et al., 1987a; De Esch et al., 1999; hydrophobic cyclic group with Phe198 in TM5, Tyr189 in Kovalainen et al., 1999). The replacement of the histamine ECL2, or Trp110 in TM3 (Levoin et al., 2008 (Fig. 5). amine group by an isothiourea group led to the very potent and Extension of the ethylamine side chain, derived from the selective H3R agonist imetit (Garbarg et al., 1992), and other imidazolyl piperidine compounds by varying the piperidin- histamine analogs with a piperidine ring in the side chain, substituting groups, resulted in drugs devoid of agonist such as immepip, showed improved affinity and efficacy at the activity and led to the antagonist thioperamide (Arrang H3R (Fig. 6; Table 2). Modifications in the piperidine nitrogen, et al., 1987a). The more potent antagonist clobenpropit was like VUF-5681, resulted in decreased affinity and functional derived from imetit through the benzylation of the isothiourea

activity (Shih et al., 1998; Kitbunnadaj et al., 2003, 2005). The group and other modifications, and its iodinated analog Downloaded from H4R has high homology to the H3R and also high affinity for (iodophenpropit) is also a potent antagonist (van der Goot H3R agonists, such as imetit and immepip. The search for and Timmerman, 2000). Other imidazole-containing antago- more selective ligands led to methimepip (N-methyl-substituted nists are referred to in Table 3. immepip), which retains high affinity and efficacy (Tables 2 The discovery of H3R constitutive activity led to the and 3) and shows 2000-fold selectivity for the hH3Roverthe reclassification of some antagonists as inverse agonists or hH R (Kitbunnadaj et al., 2003, 2005). protean ligands. Thioperamide and ciproxifan, classically

4 molpharm.aspetjournals.org at ASPET Journals on October 1, 2021

Fig. 5. Binding sites of agonists and antagonists at the human H3R of 445 aa (hH3R445). (A) Molecular docking of the endogenous agonist histamine in a model of the hH3R445 in the active state. Residues Glu206 and Asp114 are pivotal for agonist binding. (B) Planar view of the histamine binding pocket in the hH3R445.(C) Proposed binding site of a protean ligand (proxyfan) in the inactive hH3R445 as observed by molecular docking, depicting the three functional groups of the ligand important for binding (nitrogen-containing ring, central electronegative group and aromatic ring). (D) Planar view of the suggested binding residues for an antagonist at the hH3R445. 664 Nieto-Alamilla et al.

Fig. 6. Structure of H3R agonists.

considered antagonists, also behave as inverse agonists. promote the wake state, and have procognitive effects (Barbier Downloaded from Proxyfan acts as agonist, inverse agonist, or neutral antago- et al., 2004; Esbenshade et al., 2005; Fox et al., 2005; Medhurst nist, depending on the level of H3R constitutive activity, and is et al., 2007). therefore considered a protean ligand (Morisset et al., 2000; The imidazole-containing compounds display similar affin- Rouleau et al., 2002; Arrang et al., 2007). ities for the H3R across species (see Tables 2 and 3). Neverthe- Non-imidazol Antagonists. The effects of H3R activation less, some antagonists, such as thioperamide or ciproxifan, are on physiologic and pathologic conditions are the main focus of less potent at the hH3R than at the rat H3R, and as mentioned molpharm.aspetjournals.org research into the therapeutic potential of selective H3R previously, these differences have been attributed to changes ligands; however, the imidazole ring reduces penetration of in two residues located in TM3 (T119A and A122V). In the blood-brain barrier (Young et al., 1988), and imidazole- contrast, the non-imidazole compounds are more potent and based drugs inhibit the hepatic (Ishikawa selective at the hH3R (West et al., 1999; Ligneau et al., 2000; et al., 2010). To avoid these side effects, antagonists lacking Parsons and Ganellin, 2006). Furthermore, binding studies the imidazole ring, but still capable of forming a hydrogen with thioperamide and burimamide in rat, human, and bond with Glu206, were synthesized (Fig. 7). The first two non- monkey tissues indicate the presence of high- and low- imidazole antagonists were UCL1972 and VUF5391, where affinity sites, which could be related to either different states the imidazole ring was replaced for a piperidine or pyrrolidine of the same receptor or to the expression of more than one at ASPET Journals on October 1, 2021 group, respectively. The heterocyclic nitrogen interacts with isoform (West et al., 1990, 1999). Glu206, the central oxygen forms a salt bridge with a hydroxyl- containing residue, and the heterocyclic moiety establishes Function p-stacking interactions (Ganellin et al., 1998, Menge et al., 1998; Levoin et al., 2008). Presynaptic Effects

By exploration of the structure-activity relationship, a The best-known function of the H3R is the presynaptic series of highly potent and selective non-imidazole antago- regulation of neurotransmitter release in the CNS and nists were developed, including ABT-239, JNJ-5207852, NNC peripheral nervous system. This regulation has been reported 38-1049, and GSK189254, which show antiobesity properties, for histamine itself, noradrenaline, dopamine, acetylcholine

Fig. 7. Structure of H3R antagonists. Histamine H3 Receptor 665

(ACh), GABA, glutamate, serotonin (5-HT), and some neuro- release evoked by electrical or chemical stimulation (Schlicker . Whereas the evidence for a direct action of H3Rs is et al., 1988; Fink et al., 1990; Threlfell et al., 2004). By consistent for most of these , this is not contrast, in rat olfactory bulb slices, H3R activation had no established for ACh and dopamine. effect on depolarization-induced [3H]-5-HT release (Aquino- Histamine. The observation that histamine inhibited its Miranda et al., 2012). own release led to identification of the H3R by Arrang et al. Dopamine. In mouse striatum and rat substantia nigra 3 (1983). Control by presynaptic H3Rs of histamine release has pars reticulata (SNr), depolarization-evoked [ H]-dopamine been shown for slices of rat cerebral cortex, striatum, hippo- release is inhibited by H3R activation (Schlicker et al., 1993; campus, and hypothalamus, as well as for rat cerebrocortical Garcia et al., 1997), suggesting that the receptor resides on synaptosomes (Arrang et al., 1983, 1985a,b). In vivo micro- the terminals and of the nigro- dialysis experiments have shown that H3R agonists reduce striatal neurons; however, H3R activation had no effect histamine release in the rat hypothalamus and cerebral on depolarization-evoked [3H]-dopamine release from rat and cortex, whereas antagonists increased the release in the rabbit striatal slices (Smits and Mulder, 1991; Schlicker et al., hypothalamus, nucleus basalis magnocellularis, and cerebral 1993), indicating differences between species and brain cortex (Jansen et al., 1998; Lamberty et al., 2003; Giannoni regions. et al., 2009). In microdialysis studies, H3R activation increases the

Acetylcholine. Modulation of transmission extracellular dopamine levels in rat prefrontal cortex, but Downloaded from by H3Rs was first reported for the peripheral nervous not in the striatum (Fox et al., 2005; Medhurst et al., 2007). system; histamine and H3R agonists inhibited the electri- The systemic or local administration of H3R antagonists cally evoked contraction of guinea pig ileum strips but had augments dopamine release induced by no effect on the action of exogenous ACh (Trzeciakowski, in the nucleus accumbens; however, the effect of the local 1987). It was later shown that in the longitudinalis smooth perfusion of the antagonists was lower than that produced by muscle/mienteric plexus preparation, release of [3H]-ACh their systemic administration (Munzar et al., 2004), casting molpharm.aspetjournals.org induced by electrical stimulation was reduced by H3R doubt on the presence of H3Rs on the terminals of ventral activation (Poli et al., 1991). tegmental area neurons, the main source of dopaminergic 1 3 In the CNS, H3R activation inhibited K -induced [ H]-ACh innervation to nucleus accumbens (Wise, 2004). release from rat entorhinal cortex slices, but this effect was not Glutamate. Presynaptic H3Rs inhibits glutamatergic detected in synaptosomes from the same region or in slices transmission in the rat hippocampus, striatum, basolateral from the hippocampus (Arrang et al., 1995; Alves-Rodrigues amygdala, thalamus, and globus pallidus (Doreulee et al., et al., 1998), questioning the presence of the receptor on 2001; Jiang et al., 2005; Garduño-Torres et al., 2007; Osorio- cholinergic nerve terminals. In vivo microdialysis shows that Espinoza et al., 2011). In rat striatal and thalamic synapto- H3R activation reduces ACh release in the rat frontoparietal somes, H3R stimulation reduces both glutamate release and cortex, hippocampus, nucleus accumbens, and basolateral an increase in the intracellular Ca21 concentration induced by at ASPET Journals on October 1, 2021 amygdala (Blandina et al., 1996; Prast et al., 1999; Passani depolarization (Molina-Hernández et al., 2001; Garduño- et al., 2001; Bacciottini et al., 2002). These studies also suggest Torres et al., 2007). Optogenetic experiments confirmed the involvement of trans-synaptic effects; for example, H3R- H3R-mediated inhibition of corticostriatal and thalamostria- mediated inhibition of GABA or dopamine release could tal glutamatergic transmission, and the increased paired- subsequently relieve the inhibitory control by these transmit- pulse ratio supports the presynaptic location of H3Rs in ters of ACh release (Schlicker et al., 1993; Garcia et al., 1997; corticostriatal and thalamostriatal . Of note, H3R Prast et al., 1999). activation had no effect on the plasticity of corticostriatal Noradrenaline. H3R-mediated inhibition of noradrena- synapses, but the thalamostriatal synapses became signifi- line release has been reported for both the CNS and the cantly facilitatory (Ellender et al., 2011). peripheral nervous system. In cardiac sympathetic terminals, GABA. In slices from rat SNr and striatum, the activation H3R stimulation reduces noradrenaline release by various of dopamine D1 receptors, coupled to Gas proteins, enhances mechanisms, including inhibition of voltage-activated Ca21 depolarization-evoked [3H]-GABA release, and this effect is 1 and Na channels, reduction of NHE activity, and trans- selectively counteracted by H3R-mediated inhibition of P/Q- activation of prostanoid receptors (Endou et al., 1994; type voltage-activated Ca21 channels (Garcia et al., 1997; Imamura et al., 1995, 1996; Hatta et al., 1997; Mazenot Arias-Montaño et al., 2001, 2007). Likewise, in the nerve et al., 1999; Silver et al., 2002; Seyedi et al., 2005; Levi et al., terminals of striatopallidal neurons, H3R activation counter- 2007). acts the facilitatory action of adenosine A2A receptors (A2ARs), For the CNS, in vitro experiments indicated that which are also coupled to Gas proteins (Morales-Figueroa 3 H3R activation reduces depolarization-induced [ H]- et al., 2014). noradrenaline release in rodent cerebral cortex, spinal cord, H3R-mediated inhibition of GABA release has been ob- cerebellum, hippocampus, hypothalamus and olfactory bulb, served in vivo in rat medial vestibular nucleus and in vitro in and human cerebral cortex (Schlicker et al., 1989, 1992, 1994, primary cultures of rat cerebrocortical neurons and dissoci- 1999; Celuch, 1995; Timm et al., 1998; Aquino-Miranda ated neurons from the rat hypothalamus ventromedial nu- et al., 2012). In vivo microdialysis experiments showed that cleus (Jang et al., 2001; Bergquist et al., 2006; Dai et al., 2007). H3R activation reduces noradrenaline release in rat hippo- In contrast, H3R activation does not modify depolarization- campus and cerebral cortex (Di Carlo et al., 2000; Medhurst evoked [3H]-GABA release from rat thalamus and olfactory et al., 2007). bulb slices (Garduño-Torres et al., 2007; Aquino-Miranda 5-Hydroxytryptamine. In rat cerebral slices and synap- et al., 2012), indicating that not all GABAergic neurons tosomes as well as in SNr slices, H3R activation inhibits 5-HT express presynaptic H3Rs. 666 Nieto-Alamilla et al.

Neuropeptides. Histamine inhibits nonadrenergic/ negative modulator of agonist binding to and signaling of noncholinergic contraction of the bronchial and intestinal dopamine receptors. smooth muscle (Ichinose and Barnes, 1989; Taylor and The first insight into H3R/D1R interactions came from Kilpatrick, 1992), and H3R activation reduces substance functional studies where the H3R inhibited D1R-mediated P release from sensorial nerve terminals of the rat hindpaw facilitation of GABA release in SNr and striatum slices (Ohkubo et al., 1995) and the release of the gene- (Garcia et al., 1997; Arias-Montaño et al., 2001). In a related from the periarterial nerve terminals of the rat heterologous expression system, H3R activation induces a mesenteric artery (Sun et al., 2011). shift from cooperative to a noncooperative binding of D1R agonists, which indicates that an intramembrane crosstalk Postsynaptic effects occurs between these receptors. In contrast, D1R stimulation did not modify agonist binding to H Rs. A change in the D R There is evidence for postsynaptic H Rs in some areas of the 3 1 3 signaling pathway from Ga to Ga was also observed in brain, namely, striatum, cerebral cortex, hippocampus, nu- s i/o cAMP formation assays. Furthermore, H R activation did not cleus accumbens, lateral hypothalamus, and zona incerta 3 induce 42/44-MAPK phosphorylation but did so when the D R (Pillot et al., 2002; González-Sepúlveda et al., 2013; Panula 1 was coexpressed. H R antagonist prevented the effect of a D R and Nuutinen, 2013; Parks et al., 2014). 3 1 agonist and vice versa (Ferrada et al., 2009), and cross- Activation of the MAPK and Akt Pathways. The

antagonism in rat striatal slices of wild-type and D R-KO Downloaded from detection of 42/44-MAPK phosphorylation upon the activation 1 mice suggests that the interaction also occurs in vivo. The of the rat H R led to the discovery of the link between H Rs 3 445 3 phosphorylation of 42/44-MAPKs appears to be a particular and the MAPK pathway (Drutel et al., 2001), which was also print of the H R/D R interaction, as this effect was not observed for native receptors (Mariottini et al., 2009). In rat 3 1 observed in D R-MSNs. In addition, behavioral analysis hippocampus slices, H R activation stimulates the MAPK 2 3 showed that a H R antagonist enhanced D R-induced locomo- pathway in CA3 pyramidal cells, and MAPK activation seems 3 1 tor activity (Ferrada et al., 2008; Moreno et al., 2011). to be required for H R-induced improvement and molpharm.aspetjournals.org 3 The H R/D R interaction is supported by Förster Resonance consolidation in after contextual conditioning 3 2 Energy Transfer analysis in transfected cells and by binding (Giovannini et al., 2003). studies in which H R activation reduced agonist affinity of the In transfected SK-N-MC cells, hH R activation stimulates 3 3 D R high- and low-affinity sites in sheep striatal membranes the activity of the Akt/GSK3b axis (Bongers et al., 2007c), and 2 (Ferrada et al., 2008). The lack of synergism in D R- and H R- in rat cortical neurons, H R stimulation results in the 2 3 3 stimulated [35S]-GTPgS binding in rat striatal membranes phosphorylation of Akt at Ser473 and GSK3b at Ser9, via (Humbert-Claude et al., 2007), however, argues against a PI3K and MAPK activation (Mariottini et al., 2009). Akt direct H R/D R interaction. regulates the expression of apoptosis inhibitors such as Bcl-2 3 2 The Gas-coupled A2AR is highly expressed and distinctively and Bcl-x and thus promotes neuronal cell survival (Song at ASPET Journals on October 1, 2021 limited to D R-MSNs. A R activation inhibits GABA release et al., 2004), and in rat cortical neurons, H Ractivation 2 2A 3 from MSN collaterals (Kirk and Richardson, 1994), but in the increases the expression of Bcl-2 in an Akt-dependent manner. striatopallidal projections, facilitates the release of the neu- The Akt/GSK3b pathway plays a relevant role in regulating rotransmitter (Mayfield et al., 1993). The latter effect is several important cellular processes, including cell plasticity functionally opposed by H R activation, which also decreases and survival, proliferation, and , and H R 3 3 A R affinity for the agonist CGS-21680 in membranes from activation exerts a protective effect against serum deprivation- 2A globus pallidus synaptosomes, suggesting a direct, protein- induced cell death in rat cortical neurons and NMDA-induced protein interaction between A Rs and H Rs (Morales- neurotoxicity in mixed cultures of mouse cortical cells through 2A 3 Figueroa et al., 2014). the activation of the PI3K-Akt pathway (Mariottini et al., 2009). GIRK Activation. In MCH-producing neurons located in H3Rs and Neurologic and Psychiatric Disorders the rodent lateral hypothalamus, H R activation stimulates 3 The H R is a potential drug target for the treatment of GIRKs and inhibits neuronal firing (Parks et al., 2014). 3 several important neurologic and psychiatric disorders, and this aspect will be discussed briefly in reference to AD, attention- H3R Heterodimerization and Functional Consequences deficit hyperactivity disorder, PD, GTS, , addic- GPCR dimerization is now a well-accepted phenomenon tion, and sleep disorders. that can be defined as a transitory state in which, through Parkinson Disease. PD is a progressive neurodegenera- protein-protein interactions, a GPCR can alter the binding, tive that primarily results from the death signaling, or desensitization of the second GPCR that it is of substantia nigra pars compacta (SNc) dopaminergic neu- dimerized with. Although this phenomenon has been de- rons. In addition, the noradrenergic, cholinergic, and seroto- scribed as temporarily, short-lived, and the result of stochastic nergic systems are also affected and may contribute to the interactions, it has sufficient impact to cause or modify a disorder. Parkinsonian symptoms include bradykinesia, mus- physiologic output (Milligan, 2006; Calebiro et al., 2013). cular rigidity, rest , and postural and gait impairment Because of its heteroreceptor nature, the H3R is coexpressed (Moore et al., 2005; Kalia and Lang, 2015). with a large number of GPCRs in different neuronal popula- As discussed previously, H3Rs modulate striatal GABAergic, tions. For example, in striatal medium-sized spiny neurons glutamatergic, and dopaminergic transmission at the pre- (MSNs), H3Rs coexist with dopamine D1 (D1R) or D2 (D2R) synaptic and postsynaptic levels, in addition to controlling receptors (González-Sepúlveda et al., 2013), allowing for the release of GABA, glutamate, and 5-HT in several other heterodimer formation. In both interactions, H3R acts as a nuclei of the . In hemiparkisonian rats, H3R Histamine H3 Receptor 667 levels increase in the striatum and SNr ipsilateral to the (Alves-Rodrigues et al., 1996; Green and Maayani, 1977; lesioned SNc. Postmortem analysis of PD patients shows Richelson and Souder, 2000). This information suggests that increased histaminergic innervation to SN, augmented hista- the histaminergic system plays a role in the disease. mine levels in caudate/putamen, globus pallidus, and SN; Schizophrenia is characterized by the hyperactivity of higher H3R density in the SNr; and increased H3R mRNA in dopaminergic neurons and the hypoactivity of glutamatergic the external globus pallidus (reviewed in Panula and Nuutinen, neuronal cells. H3R antagonists/inverse agonists attenuate 2013). Injection of the H3R agonist immepip into the SNr -mediated facilitation of locomotor sensiti- reverses -induced contralateral turning behavior zation (Clapham and Kilpatrick, 1994) and locomotor hyper- in hemiparkinsonian rats, whereas in naive animals the activity resultant from blockade of NMDA receptors (Faucard compound induces ipsilateral turning (García-Ramírez et al., et al., 2006; Mahmood et al., 2012). In DBA/2 mice, adminis- 2004). In hemiparkinsonian rats, apomorphine-induced turn- tration of a H3R antagonist/inverse agonist reduces the ing behavior is enhanced by the systemic administration of natural deficits in sensorimotor gating (Fox et al., 2005). L-histidine and reduced by inhibiting histamine synthesis Although the evidence in animal models supports the anti- (Liu et al., 2008). psychotic properties of H3R antagonists, two clinical trials Dopamine-replacement therapy has dominated the treat- with ABT-288 and MK-0249 failed to improve the cognitive ment of PD motor symptoms since the early 1960s; however, function in schizophrenic patients (Egan et al., 2013; Haig

chronic administration of the dopamine precursor L-DOPA et al., 2014). Downloaded from results in severe side effects, particularly dyskinesias related Addiction. Addiction is a compulsive and persistent de- to excessive D1R-mediated signaling in the basal ganglia pendence on behaviors or substances in which the reward (Santini et al., 2007). In parkinsonian marmosets, the sys- brain circuitry (the dopaminergic mesocortico-limbic system) temic administration of immepip exacerbates the symptoms plays a major role. HDC-KO mice show increased in nontreated animals, but in L-DOPA-treated marmosets, it tolerance and reduction in the place-preference test. Con- reduces the total dyskinesia score without affecting the anti- versely, HDC-KO mice show an increase in -evoked molpharm.aspetjournals.org parkinsonian action (Gomez-Ramírez et al., 2006). Altogether, conditioned place preference and consumption (Zimatkin and the available information indicates a role for histamine and Anichtchik, 1999). Substances like alcohol, cocaine, and the H3R in PD and a potential use for drugs morphine modulate histamine synthesis, release, and turn- acting at the receptor in the treatment of both the disease and over (Nishibori et al., 1985; Ito et al., 1997), suggesting the complications of the pharmacologic therapies. involvement of the histaminergic system in addiction process- Gilles de la . GTS is a disorder es. In H3R-KO mice, a reduction in alcohol-induced place characterized by motor and phonic tics (echolalia, echopraxia, preference and consumption is observed, and a similar effect is and coprolalia), sensory and cognitive symptoms, and comor- induced by H3R blockade, indicating the participation of the bidities such as obsessive-compulsive and attention-deficit H3R in alcohol addiction (Brabant et al., 2007; Nuutinen et al., hyperactivity disorders (Shan et al., 2015). GTS is related to 2010; Galici et al., 2011). at ASPET Journals on October 1, 2021 the dysfunction of the corticostriatal-thalamic-cortical cir- Hyperactivity caused by /methamphetamine cuitry and involves the transmitters dopamine, noradrena- is attenuated by the H3R antagonists thioperamide, ciproxifan, line, 5-HT, and histamine (Panula and Nuutinen, 2013; pitolisant (BF2.649), and ABT-239 (Clapham and Kilpatrick, Rapanelli and Pittenger, 2016). 1994; Fox et al., 2005; Ligneau et al., 2007a,b; Motawaj A mutation (W317X) in one of the HDC gene alleles is and Arrang, 2011); however, other antagonists (GSK-207040, associated with the familiar occurrence of GTS (Ercan- JNJ-5207852, and JNJ-10181457) failed to replicate this re- Sencicek et al., 2010). HDC-knockout mice, with brain hista- sponse (Komater et al., 2003; Southam et al., 2009). Moreover, mine levels almost negligible in homozygote animals, exhibit thioperamide and clobenpropit increased methamphetamine stereotypic movements and spontaneous tic-like symptoms self-administration (Munzar et al., 2004). On the basis of the after the intraperitoneal injection of amphetamine (Castellan previously described cross-talk between the dopaminergic Baldan et al., 2014), supporting the involvement of the and histaminergic systems and the direct modulation of histaminergic system in GTS. histaminergic transmission by addictive drugs, targeting the Schizophrenia. Schizophrenia is a mental disorder de- histaminergic neurons is a plausible therapeutic proposal. fined by positive symptoms (hallucinations, delusions, and Attention-Deficit Hyperactivity Disorder. Most prev- thought and movement disorders), negative symptoms (re- alent in children, attention-deficit hyperactivity disorder is duced feelings, difficulty to initiate and maintain activities, characterized by an ongoing pattern of inattention and/or and reduced speaking), and cognitive symptoms (poor un- hyperactivity-impulsivity. This disorder affects several neu- derstanding of information, trouble focusing, and problems rotransmitter systems, mainly the dopaminergic, noradren- with ) (Flores et al., 2016). ergic, cholinergic, and systems (Vohora and In schizophrenic patients, H3R receptor expression is in- Bhowmik, 2012). H3R antagonists enhance the release of creased in the prefrontal cortex and decreased in the hippo- neurotransmitters involved in cognition, including ACh and campus, areas closely related to memory and cognitive dopamine in the prefrontal cortex; ACh, dopamine, and processes (Jin et al., 2009). An increase in the histamine noradrenaline in the cingulate cortex; and ACh in the metabolite telemethylhistamine was reported for chronic hippocampus (Fox et al., 2005; Medhurst et al., 2007; patients (Prell et al., 1995), and drugs affect Ligneau et al., 2007b). In rodents, the proattentional and the activity of the histaminergic neurons by acting at dopa- procognitive actions of these drugs suggest that these com- mine, 5-HT, and glutamate (NMDA) receptors expressed pounds have a potential therapeutic use in this disorder by these neurons (Javitt and Zukin, 1991; Morisset et al., (reviewed by Passani and Blandina, 2011; Vohora and 1999, 2002) and by antagonizing H1,H2, and H3 receptors Bhowmik, 2012); however, the H3R antagonist bavisant 668 Nieto-Alamilla et al.

1 (JNJ-31001074) did not show clinical effectiveness in human resting leak K conductance (IKL), which results in prolonged adults with attention-deficit hyperactivity disorder, whereas depolarization of thalamocortical neurons, leading to inhibi- both atomoxetine and induced improvement tion of burst firing and the promotion of single-spike firing. (Weisler et al., 2012). This action abolishes sleep-related activity in thalamocortical Alzheimer Disease. AD is a progressive neurodegenera- networks and facilitates the single-spike activity typical of the tive brain disorder resulting in the loss of memory and waking state (McCormick and Bal, 1997). cognitive functions that is often accompanied by behavioral Impaired wakefulness and increased sleep are observed disturbances like and depression (Querfurth and after the inhibition of histamine synthesis and in HDC-KO LaFerla, 2010). The pathologic hallmarks of AD include the mice (Parmentier et al., 2002). The wake-promoting activity accumulation of the protein b-amyloid (Ab), which leads to the of histamine is shared by a variety of H3Rantagonists/ production of extracellular Ab plaques and hyperphosphor- inverse agonists (Gao et al., 2013). H3Rs presynaptically ylation of the protein t. This in turn results in the formation of modulate the release of histamine and other neurotransmit- intracellular neurofibrillary tangles and the massive loss of ters that participate in the wake-sleep cycle and postsynap- cholinergic neurons (Brioni et al., 2011). tically reduce the excitability of MCH-producing neurons In AD patients, neurofibrillary tangles occur in the TMN, that are also involved in the cycle (Parks et al., 2014). along with a significant loss (∼50%) of the histaminergic H3R-KO mice present a wide-range of apparently contradic-

neurons (Nakamura et al., 1993; Shan et al., 2015); but the tory wake-sleep alterations; the animals show wake de- Downloaded from latter effect is not matched by the reduction (224%) in HDC ficiency and sleep deterioration but also display signs of mRNA expression, suggesting that enhanced histamine pro- enhanced vigilance (Gondard et al., 2013). duction by the remaining neurons compensates the cell loss. Histaminergic neurons are activated by the Some reports indicate that brain histamine levels are reduced hypocretin, and type 1 is characterized by exces- in hypothalamus, hippocampus, and temporal cortex from sive daytime sleepiness and . The main cause of AD patients, although others show an increase in the same type 1 narcolepsy is the loss of hypocretinergic neurons; molpharm.aspetjournals.org cerebral regions, together with frontal, parietal, and occipital however, an increase in the number of histaminergic neurons cortices. Furthermore, H3R mRNA levels seem to be higher in has been reported (Valko et al., 2013). Although histamine the prefrontal cortex only in female AD patients, indicating a dysregulation is not central to the pathophysiology, H3R gender-dependent change (Shan et al., 2015). In this regard, antagonists/inverse agonists such as pitolisant are useful for differences in histamine levels in AD and normal brains may the treatment of excessive sleepiness disorders, namely, originate from methodologic issues, genetic background, time- narcolepsy and idiopathic hypersomnia, by improving alert- elapsed between death and analysis, and proper diagnosis; ness (Lin et al., 2008; Inocente et al., 2012; Dauvilliers et al., however, measurement of histamine content with a sensitive 2013). Furthermore, pitolisant reduces sleepiness in PD HPLC fluorimetric method in brains from controls and AD patients without interfering with anti-parkinsonian drugs patients, with matched age and postmortem time, found a (Schwartz, 2011). On March 2016, pitolisant (Wakix) was at ASPET Journals on October 1, 2021 significant decrease in the hypothalamus (258% of control approved in the European Union for the treatment of values), hippocampus (257%), and temporal cortex (247%) in narcolepsy with or without cataplexy in adults, becoming AD brains (Panula et al., 1998). thus the first drug acting at H3Rs that reachs the market H3R activation could account for the diminished release of (Syed, 2016). noradrenaline and ACh in the prefrontal cortex, both trans- mitters with an important role in cognition (Blandina et al., Final Remarks 1996; Schlicker et al., 1999). Based on studies with transgenic mice, it may be hypothesized that neurotransmitter release The histaminergic system exerts a significant modulatory evoked by H3R antagonists leads to postsynaptic effects, such effect on different brain functions, from movement to cogni- as the phosphorylation of the cAMP response element binding tive processes. The H3R plays a key role in this effect through protein, a related to cognitive function, or its wide expression and action as a modulator of several the inhibition of GSK3b, responsible for tau hyperphosphor- neurotransmitter systems. Although the main effects of H3R ylation in AD (Hooper et al., 2008; Bitner et al., 2011). These activation are known for some brain areas, such as the in vivo studies raise the possibility that H3R antagonists striatum and the hippocampus, its actions in other areas indirectly modulate signaling pathways, resulting in symp- have yet to be fully explored. Furthermore, determining the tomatic alleviation in AD patients. H3R antagonists like precise H3R expression in distinct cells of several neuronal PF-03654746, GSK189254, MK-0249, ABT-239, and ABT- circuits, such as the corticostriato-thalamocortical and 288 bind the hH3R with high affinity (Ki 0.2 to 3.2 nM), and mesocortico-limbic circuits, will help understand the partici- some have advanced to clinical trials (Brioni et al., 2011; pation of the histaminergic system in aspects—such as the Sadeq et al., 2016). control of motor activity, cognition, and the sleep-wake cycle— Sleep Disorders. The brain circuitry that regulates sleep- and certain disorders, including PD, AD, and addiction. wake cycle in mammals comprises cell groups in the thalamus, A deeper knowledge of the functional and molecular interac- brainstem, hypothalamus, and basal forebrain. The histamin- tions of H3Rs with other receptors is also important for the ergic system plays a key role in the maintenance of cortical design of novel therapeutic approaches targeting the hista- activation and wakefulness (Lin, 2000). The histaminergic minergic system, and for this purpose, the elucidation of the neurons fire tonically, are more active during wakefulness, H3R crystal structure will represent an important discovery. and send widespread inputs to areas crucially implicated in Finally, more clinical studies are needed to evaluate or confirm sleep-wake control, for instance, the cerebral cortex and the usefulness of H3R ligands in several neuropsychiatric thalamus. In the latter region, H1R activation decreases a disorders. Histamine H3 Receptor 669

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