5-HT Receptor Nomenclature: Naming Names, Does It Matter? A

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5-HT Receptor Nomenclature: Naming names, does it matter? A tribute to Maurice Rapport. Daniel Hoyer ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.7b00011 • Publication Date (Web): 07 Mar 2017 Downloaded from http://pubs.acs.org on March 8, 2017

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ACS Chemical Neuroscience

5-HT Receptor Nomenclature: Naming names, does it matter? A tribute to Maurice Rapport.

Daniel Hoyer

Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia

The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, Victoria 3052, Australia

Department of Molecular Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA

Abstract:

The naming of 5-HT receptors has been challenging, especially in the early days when the concept of multiple receptors for a single neurotransmitter was considered to be unrealistic at best. Yet pharmacological (rank orders of potency in functional or biochemical settings) and transductional evidence (2nd messengers, electrophysiology) clearly indicated the existence of receptor families and subfamilies. The genetic revolution, with the cloning and study of recombinantly expressed receptors, and eventually the cloning of the human and other genomes have made such reservations obsolete. Further, the advances in structural biology, with the possibility to study ligand receptor complexes as crystals and/or using solution NMR have largely confirmed the complexity of the 5-HT receptor system: species differences, existence of multiple receptor active and inactive states, splice variants, editing variants, complexes with multiple interacting proteins and transduction bias. This is a short personal history on how advances in biochemistry, molecular biology, biophysics, imaging and medicinal chemistry, some lateral thinking and a decent amount of collaborative spirit within the 5-

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HT receptor nomenclature committee and the 5-HT community at large, have helped to better define the pharmacology of the 5-HT receptor family.

Key words: serotonin, 5-HT, 5-hydroxytryptamine, receptors, serotonin club, nomenclature, IUPHAR

Introduction:

The nomenclature of 5-HT receptors has a long and rather convoluted history. Maurice Rapport after synthesizing 5-HT (5-hydroxytryptamine, serotonin) realized that enteramine (as described in the 1930’s by Erspamer and colleagues) and 5-HT were identical (1-3). Shortly after that seminal discovery, 5-HTD and 5-HTM receptors were distinguished by Gaddum & Picarelli (4) in the guinea pig ileum, still quite an achievement, since most 5-HT receptors are expressed in the ileum. S1/S2 or 5HT1/5-HT2 binding was then described in the late 1970s, (i.e. S. Peroutka, S. Snyder, G. Fillion, D. Nelson, N. Pedigo, M. Hamon, J. Leysen and P. Laduron). 5-HT2 was also referred to as the “neuroleptic” receptor (5). In an attempt to reconcile classical and more molecular aspects of pharmacology (functional tissue work versus radioligand binding and second messenger studies), the existence of distinct 5-HT1-like, 5-HT2 and 5-HT3 receptors was eventually acknowledged by Philip Bradley and colleagues (6), the result of a consensus meeting held in 1984 around the IUPHAR meeting in London. There was already clear evidence for subtypes of 5-HT1 and 5-HT2 receptors, based on rank orders of potency in binding and second messenger studies when the Bradley report was published, but such a level of distinction was complex and the concept of receptor families with classes and subclasses, was not to be accepted that rapidly by the scientific community. However, 1986 was a turning point with the cloning and molecular characterisation of the first GPCR, namely the beta2 adrenoceptor by the group of Bob Lefkowitz (7). An interesting event happened then, in that the second GPCR to be cloned, G21, was an orphan for a short while, until it was realised that it corresponded to the 5-HT1A receptor (8). It is only then, that by homology cloning based on G21 the beta1 receptor was subsequently cloned and characterised (9). This illustrates the close relationship between 5-HT1 receptors and beta adrenoceptors, as suggested from earlier binding studies: indeed, at least 5-HT1A and 5-HT1B receptors had significant affinity for a number of beta receptor antagonists. In fact [125I]cyanopindolol (my PhD thesis subject: 10-12) was used to characterise 5-HT1B receptors, at least in rodent binding studies and 5-HT autoreceptor work (13-16). At the same time, our esteemed colleague and friend, Paul Vanhoutte, after creating the Serotonin Club, started modernizing IUPHAR and established receptor nomenclature committees.

The role of the Serotonin club (now International Society for Serotonin Research) and the 5-HT receptor nomenclature committee:

The inaugural meeting of the club, took place on Heron Island, as a satellite to the Sydney IUPHAR 1987 meeting. This was to be followed by many such meetings: we have celebrated the 25th anniversary in July 2012 in Montpellier, in the meantime we have also been to Cape Town (2014) and


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Seattle (2016). The IUPHAR Receptor Nomenclature Committee was established at the same time, also led by Paul Vanhoutte: the 5-HT receptor nomenclature committee was one of the first committees of many to follow. We would have regular meetings at the occasion of 5-HT club gatherings, often in conjunction with IUPHAR, EPHAR, SFN and/or BPS meetings (see below). The 5HT receptor nomenclature business had started a little earlier, at the IUPHAR 1984 meeting in London, where a group of 5-HT experts convened and decided to tackle a few issues with receptor names, such as unifying S1, S2, 5-HT1, 5-HT2, 5-HTM and 5-HTD receptors, and preparing the future (6). In retrospect, since I was not part of these discussions, I feel that the move was rather conservative: the proposal was to agree on naming serotonin receptors, “5-HT1 like”, 5-HT2 (5-HTD) and 5-HT3 (5HTM). There was acknowledgement that the situation is more complex, e.g. 5-HT1 like receptors were accepted, but the subdivision of 5-HT1 receptors into subtypes was not ready, although ample evidence suggested that at least 5-HT1A, 5-HT1B, 5-HT1C were clearly defined and functional receptors.

We formally met for the first time in Basel at the 1990 Serotonin Meeting with Paul Hartig, Pat Humphrey, Terri Branchek, Pramod Saxena, John Fozard amongst others, to constitute the 5-HT nomenclature committee (to be led by Pat Humphrey, see cover of the meeting in the abstract). We were to tackle the issue of 5-HT receptor complexity / diversity, and make recommendations that were to apply to other receptor families: in essence, our task was to “naming names” or invent a common language. The resulting activities were frantic, enthusiastic, collegial and facilitated by advances in the molecular biology of GPCRs and ligand-gated channels, such as 5-HT3 or GABAA. In addition, our medicinal chemists colleagues synthesised an ever increasing number of ligands with high affinity and selectivity for various 5-HT receptors, some of which became powerful drugs. Since much knowledge was covered by company IP, not everything could be revealed, but it was agreed amongst that group, not to lead the “competition” on the wrong track. By 1993, we proposed structural, transductional and operational principles to be applied to the 5-HT receptor nomenclature (17,18). By 1994, the official nomenclature paper was sanctioned by IUPHAR and published (19). In 1996/97, we recommended alignment with the human genome (20-22) and further refinements were made in the following years (23). The proposed nomenclature was widely and rather rapidly adopted. Many of the recommendations are still valid, and the principles were largely applied to other receptor families. Out of this endeavour emerged multiple successful collaborations, between researchers working in competing Pharma and Biotech or Academia. Long lasting friendships were established and cultivated in numerous 5-HT meetings, where we had the privilege to meet Maurice Rapport on several occasions (See photograph of the 2004 Porto meeting, attented by M. Rapport). That is the beauty of Science, creating knowledge by having fun and making friends.

Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PPA (1994) International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev, 46: 157-204. 23 years after.......

The introduction of the Pharmacological Reviews paper stated that "the authors had spent collectively over 100 years working on serotonin receptors". If the review were to be written today, this timeframe would be much more extensive, although some of us have pursued other interests. One of



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the most pleasing aspects of this “Journey” was the extreme diversity of the group: the authors were located and originated from Europe, America and Australasia. In addition, we had clearly different backgrounds, with colleagues from both Academia and Industry and emerging Biotech, combining classical pharmacology, medicinal chemistry and molecular pharmacology / biology, gastro intestinal, cardiovascular and brain research. Most of us still meet on a regular basis, whether in scientific meeting (as most recently at the 2016 5-HT meeting in Seattle), or privately in all corners of the world. The production of this manuscript represented a very intense effort of compiling data and confronting ideas in obscure meeting rooms, pubs, restaurants, trains and airport lounges. My account of the generation of the Pharmacological Reviews paper and follow ups, is agreeably very biased. The updated Pharmacological Reviews paper that is about to be completed, will have about 25 authors, again from different ages, cultures and backgrounds, to account for the number of receptors / splice and even editing variants, homo and heteromeric nature, and the complexity of their transduction mechanisms and multiplicity of interacting proteins.

My first exposure to 5-HT:

My background is in Biochemistry and Physiology, which translated into molecular and cellular pharmacology and eventually biomedical research and development in Industry (Sandoz, then Novartis), and a few later appointments in academic institutions (the Scripps Research Institute in San Diego, University of Melbourne and the Florey Institute, both in Melbourne). My first research interest was the study of adrenoceptors, and my PhD thesis (under the supervision of Profs. JeanClaude Stoclet and Philippe Poindron, Faculty of Pharmacy, Strasbourg) dealt with the development of specific radioligands for beta and alpha adrenoceptors: the work was all performed in the lab of Dr. Günter Engel at Sandoz in Basel (10-12, 24, 25). On the afternoon of my PhD defence, in September 1981, I presented my work at the then Marion Merrell Dow Institute in Strasbourg, to the group headed by John Fozard. John and I kept in touch, as I moved to Philadelphia a few weeks later. At that time, the teams of John Fozard in Strasbourg, Brian Richardson, Günter Engel and colleagues in Sandoz/Basel, Mike Tyers and colleagues in Glaxo/Ware, were developing the first potent and selective 5-HTM (5-HT3) receptor antagonists, namely MDL 72222, ICS 205930 (tropisetron) and GR38032 (ondansetron), respectively (26-28). I had very little background in 5-HT, but shortly before leaving Basel for Philadelphia, Jose Maria (Chema) Palacios had arrived from Johns Hopkins University, where Sol Snyder, Steve Peroutka and others developed an interest in 5-HT1 and 5-HT2 receptors (29). Chema had completed a post-doc with Mike Kuhar, and introduced receptor autoradiography as a tool to discover, characterise and study established and “new” receptor targets, primarily in the brain, including 5-HT receptors. The method would also be applied to peripheral tissues, but our main interest was in the CNS. I did my post-doctoral work with Perry Molinoff (Chair of Pharmacology) at the University of Pennsylvania Medical School, where I worked on adrenoceptor desensitisation and transduction (30). During my stay in Philadelphia, I met Steve Peroutka who was looking for a position: Steve eventually went to Stanford, but introduced us to 5-HT1 and 5-HT2 receptors. Later that year, 1982, at an ASPET meeting in Vermont, I met Paul Hartig, who was at Johns Hopkins: we discussed the utility of [125I]LSD as a tool to study 5-HT receptor. Interestingly, G. Engel had also started working with [125I]LSD and derivatives, in order to separate 5-HT M and D receptors, in other words, 5-HT2 and 5-HT3 receptors, respectively. Keep in mind that LSD had been discovered at


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Sandoz in 1943 by Alfred Hoffman (31), as were many other compounds acting on 5-HT receptors, such as ergotamine, DHE and the likes. It was not known for quite some time which targets were engaged by these compounds, since 5-HT (1,2) and especially 5-HT receptors were to be identified much later (4). In Philadelphia, Alan Frazer who was both at the VA Hospital and the departments of Pharmacology and Psychiatry at Penn, made me read my first papers on 5-HT receptors and transporters. On the other hand, John Fozard and Günter Engel did send me their own recent work as we kept in touch during my stay in the US. To be honest, I could not really get excited by 5-HT, until an offer was made by Daniel Hauser, then Head of research in Basel to join Sandoz and to work on 5HT receptors. Indeed, various members of a 5-HT taskforce lead by Brian Richardson were to spread into various departments (Cardiovascular, Neuroscience and Immunology) of the then Preclinical Research of Sandoz in Basel. The task force had discovered ICS-205930 (tropisetron, Navoban) which was to be developed for chemotherapy-induced vomiting. Thus, the interest in 5-HT was increasing steadily at Sandoz and in big Pharma more generally. Early attempts with 5-HT3 receptor antagonists in the pain field looked very promising (27) but did not materialise, neither in migraine or any other neuropsychiatric disorder for that matter, but there was clearly room for further work. Thus, our colleagues at Glaxo, Janssen, Roussel, Lilly, Merrell Dow, ICI, Welcome, Merck, were all in the 5-HT game. In addition, a number of prominent academic colleagues were engaged is successful collaborations with Pharma. When I returned to Basel, things changed rather swiftly. Chema Palacios had set up receptor autoradiography to full scale. There was a young Spanish MD/PhD in Chema’s lab, Angel Pazos, who was investigating the binding of [3H]mesulergine (and that of other radioligands) in the brain. Mesulergine was initially developed as a dopamine D2 receptor ligand, until it was found also to label 5-HT2 receptors (32). At that time, life in the 5-HT field was rather (falsely) simple: we knew from Peroutka and Snyder (29) that [3H]5HT labelled 5-HT1 sites, that [3H]spiperone (and later [3H]ketanserin) labelled 5-HT2 sites, whereas [3H]LSD labelled both. However, David Nelson and colleagues during a sabbatical in Paris with Michel Hamon (33) had already suggested that 5-HT1 binding was heterogeneous. Indeed, [3H]5-HT was displaced biphasically by spiperone: the high affinity site for spiperone was called 5-HT1A, and the low affinity 5-HT1B (incidentally, David Nelson was the first graduate student of my mentor at Penn, Perry Molinoff). Earlier, Gilles Fillion in Paris, had already shown that there are [3H]5HT binding site in the brain, and that some of these receptors were positively coupled to cAMP production (34). On the other hand, Leysen and Laduron had described the “neuroleptic receptor” (5). As we would learn much later from Joel Bockaert’s group in Montpellier (who was a member of my thesis committee), the receptors identified by Fillion were probably 5-HT4 receptors, although under certain conditions, 5-HT1A receptors may also stimulate adenylate cyclase activity in the brain (35). Further, Derek Middlemiss (36), working later with John Fozard and Mark Tricklebank in Strasbourg, had suggested that some indole beta blockers had high affinity for 5-HT receptors as well. Thus, somewhat arbitrarily, it was agreed that 5-HT1 sites had high affinity for 5-HT, whereas 5-HT2 sites had low affinity for the endogenous ligand and by extension 5HT receptor agonists. A breakthrough was reached in 1983, when Middlemiss and Fozard (37) described 8-OH-DPAT as a selective 5-HT1A ligand, and Michel Hamon and colleagues (38) reported the selective labelling of 5-HT1A sites using [3H]8-OH-DPAT. In Basel, we were describing [3H]mesulergine binding in the choroid plexus (39,40) that was displaced with high affinity by 5-HT, but not by ketanserin or spiperone, suggesting some form of 5-HT1 binding. We further compared the features of [3H]mesulergine-labelled sites with those of classical 5-HT2 binding as labelled with [3H]ketanserin (and other radioligands). We proposed the new site to be named 5-HT1C: indeed, [3H]mesulergine binding was different from 5-HT1A and 5-HT1B as evidenced in radioligand binding and



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autoradiographic studies performed in various species (39-46). 5-HT1C sites had high affinity for 5-HT and LSD (47) and a number of 5-HT2 ligands, especially antidepressants and antipsychotics. At that stage, it became clear that there were species differences in receptor pharmacology: [3H]mesulergine binding had different profiles in rodents, humans and pigs. A pattern that would repeat itself with a number of 5-HT receptors, a prominent example being the 5-HT1B receptor (13-16, 45-50). Keep in mind that in these early years, we used membranes or slices of brain, peripheral nervous and nonnervous tissue sources: 5-HT receptors were only to be cloned a few years later. We thus used rat, mouse, hamster, rabbit, guinea pig, cat, dog, bovine, human and more exotic species such as pigeons, opossum and trout (51-56). Some established cell lines also started being used such as neuroblastoma glioma cells that constitutively express 5-HT3 and other receptors, e.g. C6, NG108-15, N1E-115 or NCB20, only to find out that stable cell lines may not be stable expressors either (57, 58).

Autoradiographic and membrane binding studies were then performed in various species, including the human brain (43-46). It turned out that both, 5-HT1A and 5-HT1C binding could be documented, in addition to 5-HT2 binding, but that what was called 5-HT1B binding was absent in pig and human brain, in contrast to rodent brain; similarly, in the guinea-pig and a number of other species (see e.g. 48-51). Eventually, it turned out that only rat, mouse and opossum had a 5-HT1 receptor with a classical 5HT1B profile (see 13, 14, 50). It then became apparent that other species expressed what was called 5-HT1D receptors in the brain, i.e. guinea-pig, bovine, dog, rabbit, monkey and humans (see 48, 49, 51, 59). The pharmacology of 5-HT1B and 5-HT1D binding receptors was different, but their distribution in brain rather similar, if not overlapping and they showed similar coupling and functional patterns (59, 60). To put it simply, a 5-HT1B receptor profile was characterised by high affinity for indole beta blockers, in contrast to that of 5-HT1D.

We had established in a long standing collaboration with Manfred Goethert's group in Bonn, that rat brain autoreceptors blocking 5-HT release were of the 5-HT1B type. There was good evidence that in the hippocampus, inhibition of adenylate cyclase activity was typically of the 5-HT1A type. The 5-HT1B receptor, highly concentrated in the substantia nigra, was also negatively coupled to adenylate cyclase activity (60-62). Interestingly, the distribution of 5-HT1B and 5-HT1D sites in various species' brains was very similar, and we then found that in the bovine substantia nigra, the then called 5-HT1D receptor was also negatively coupled to adenylate cyclase (59, 52). We knew that in various species including humans, inhibitory autoreceptors displayed 5-HT1D receptor pharmacology (16). In other words, the similarities between 5-HT1B and 5-HT1D were rather compelling. After an ICNP meeting in Munich in 1988, Derek Middlemiss and I decided to put that evidence together and propose that the receptors were probably species variants (50). This was also true in the periphery, as in the same species, we could define 5-HT1B and 5-HT1D like pharmacologies (63-65) in various vascular preparations. This became an interesting matter of research and debate as sumatriptan / GR43175 was being developed as a selective “5-HT1-like” receptor agonist for the treatment of acute migraine (see 66-71). Based on the effects of GR43175 in binding, autoradiography, second messengers and various vessel preparations, we proposed that sumatriptan is a 5-HT1B/1D receptor agonist (63) as are DHE and ergotamine (54). This has been amply confirmed including in the 5-HT1B receptor crystallography studies (72,73). Whether the effects of sumatriptan are mediated by vascular receptors, neuronal receptors or an inflammation component is still a matter of debate. It is clear


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however that both 5-HT1B and 5-HT1D receptors have a neuronal localisation as well (74-78), including in the trigeminal ganglia.

On the other hand, it became evident that 5-HT2 receptors were coupled to PLC and calcium mobilisation, as were 5-HT1C receptors: the strong similarities between these receptors was becoming compelling too (79, 80). Enough to suggest that these receptors are closely and likely structurally related (81, 82) and thus form a family distinct from 5-HT1. Based on this, the cloning of the 5-HT1C receptor (83-85) was rapidly followed by that of other 5-HT2 (5-HT2A) receptors, including 5-HT2B (86-88). By then, the 5-HTM receptor was in a very different league, i.e. a ligand-gated channel, thus justifying the 5-HT3 appellation. The availability of tools (potent and selective 5-HT3 receptor antagonists such as ondansetron, granisetron, tropisetron) in combination with 5-HT2 antagonists (ketanserin and others), allowed then some rapid progress. It became possible to label and study the distribution of 5-HT3 receptors: they were found in the brain, GIT, heart, vagus nerve, ganglia and neuroblastoma cells (57,58, 89-91). Not surprisingly, 5-HT3 receptors were cloned from neuroblastoma cells (92).

The generation of the current 5-HT receptor nomenclature:

The amount of information collected in the 1980-1990’s became rapidly overwhelming, and after the IUPHAR 1987 meeting (Heron Island), thanks to Paul Vanhoutte, the serotonin club was created as well as a body to take care of nomenclature issues, that would be affiliated to IUPHAR. The club started to hold regular meeting in 1988, Amsterdam (Cardiovascular aspects, Saxena), 1989 (New York, Whittacker/ Peroutka), 1990 Basel (IUPHAR, Fozard and Saxena), 1991 Birmingham (Bradley), 1992 Houston (Vanhoutte), 1994 Chicago (IUPHAR, van de Kar), 1997 San Francisco, (Hoyer, Martin, Eglen, Hamblin and Yocca), 1998 Rotterdam and Munich (IUPHAR Saxena), 2000 New Orleans (Whittacker), 2002 Acapulco (IUPHAR, Villalón), 2004 Porto (Goethert, EPHAR), 2006 Sapporo, (Yoshioka, IUPHAR), 2008 Oxford (Sharp), 2010 Montreal, (IUPHAR), 2012 (Montpellier, Bockaert), 2014 (CapeTown, IUPHAR) and 2016 (Seattle, Neumaier) where the nomenclature committee would meet and discuss the newest findings. The next meeting will be in Cork (2018, Cryan). I have attended most of these meetings, although I officially stopped working on 5-HT in 1992! Sandoz and then Novartis were indeed rather generous in those early days. Later, I attended the meetings using private funds, which is by no means unusual; many of our colleagues continue to attend meeting well after retirement.

Following these meetings several updates were initiated, published initially in the TiPS supplements on nomenclature, or as regular articles TiPS or Neuropharmacology (17,18 21,22). Pharmacological Reviews is the main publisher of nomenclature position papers (19), although for a while the nomenclature compendia in IUPHAR media were also publishing updates (93). More recently, IUPHAR and the British Pharmacological Society, with support from the Welcome Trust, release every second year, an update on receptors and channels and further drug targets (transporters, enzymes, kinases, immunoreceptors), known collectively as the Guide to Pharmacology (see 94-97). Tables 1 and 2 attempt to give a chronological aspect of on how the 5-HT field evolved.



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Humphrey et al (17) set the scene by proposing up to seven 5-HT receptor families with subfamilies for 5-HT1, 5-HT2 and 5-HT3 receptors: this was based on operational or pharmacological (rank orders of potency for agonists and antagonists), transductional (preferred second messengers or ligandgated ion channels) and structural information (gene sequence and presumed peptide sequence). The short note read: “The revised 5-HT receptor nomenclature published here was established by the Serotonin Club Receptor Nomenclature Committee and approved by IUPHAR. The members of the Serotonin Club Receptor Nomenclature Committee are: P. B. Bradley, T. A. Branchek, D. E. Clarke, M. L. Cohen, J. R. Fozard, M. Gothert, J. P. Green, P.R. Hartig, D. Hoyer, P. P. A. Humphrey, J. E. Leysen, G. R. Martin, D. N. Middlemiss, E. J. Mylecharane, S. J. Peroutka and P.R. Saxena.”

The 1994 Pharmacological Reviews paper (19), went into much further details with extensive tables, lists of compounds, agonist and antagonist rank order of potencies, gene and transductional information, and experimental setups, as can be taken from the abstract: “It is evident that in the last decade or so, a vast amount of new information has become available concerning the various 5-HT receptor types and their characteristics. This derives from two main research approaches, operational pharmacology, using selective ligands (both agonists and antagonists), and, more recently, molecular biology. Although the scientific community continues to deliberate about the hierarchy of criteria for neurotransmitter receptor characterisation, there seems good agreement between the two approaches regarding 5-HT receptor classification. In addition, the information regarding transduction mechanisms and second messengers is also entirely consistent. Thus, on the basis of these essential criteria for receptor characterisation and classification, there are at least three main groups or classes of 5-HT receptor: 5-HT1, 5-HT2, and 5-HT3. Each group is not only operationally but also structurally distinct, with each receptor group having its own distinct transducing system. The more recently identified 5-HT4 receptor almost undoubtedly represents a fourth 5-HT receptor class on the basis of operational and transductional data, but this will only be definitively shown when the cDNA for the receptor has been cloned and the amino acid sequence of the protein is known. Although those 5-HT receptors that have been fully characterised and classified to date (and, hence, named with confidence) would seem to mediate the majority of the actions of 5-HT throughout the mammalian body, not all receptors for 5-HT are fully encompassed within our scheme of classification. These apparent anomalies must be recognised and need further study. They may or may not represent new groups of 5-HT receptor or subtypes of already known groups of 5-HT receptor. Even though the cDNAs for the 5-ht1E, 5-ht1F, 5-ht5, 5-ht6, and 5-ht7 receptors have been cloned and their amino acid sequence defined, more data are necessary concerning their operational and transductional characteristics before one can be confident of the suitability of their appellations. Therefore, it is important to rationalise in concert all of the available data from studies involving both operational approaches of the classical pharmacological type and those from molecular and cellular biology.”

Of note, 5-ht1E, 5-ht1F, 5-ht5, 5-ht6, and 5-ht7 were considered to be hypothetical entities until further evidence would be provided, and some remain as such even today, e.g. 5-ht1E and 5-ht5. The 5-HT4 receptor was well covered under the heading “other” receptors, as the cloning was only reported after the manuscript was already published (see table 2). In the meantime, the various 5-HT meetings held in Basel, Birmingham, Houston and Chicago, provided additional and extensive new information


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on recombinant receptors that were much discussed and debated (see 21): “Information concerning the structural, operational and transductional characteristics of 5-HT receptors continues to increase at an incredible pace, challenging our efforts to assimilate and organise it in a comprehensive manner. At the time of the Serotonin Satellite meeting in Chicago (1994), the IUPHAR classification of receptors for 5-HT recognised four distinct receptor classes (5-HT1, 5-HT2, 5-HT3 and 5-HT4), comprising seven fully characterised functional receptor subtypes and four recombinant receptors (5-HT1Dalpha and 5HT1Dbeta, 5-ht1E, 5-ht1F). Four additional recombinant receptors (5-ht5A, 5-ht5B, 5-ht6 and 5-ht7) provide strong evidence for the existence three additional receptor classes. Indeed, results presented largely at the Chicago meeting have confirmed the physiological importance of both 5-ht6 and 5-ht7 receptors so that in future schemes, these will be acknowledged as fully characterised receptor classes. It is evident from this brief review that a number of issues remain to be resolved, and more are certain to follow. Some, for example the definition of the term 'physiologically relevant', as applied to recombinant receptors, will long continue to attract debate, especially between molecular biologists and pharmacologists. Others, such as the issue of species primacy, are perhaps more fundamental and can be expected to receive the urgent attention of NC-IUPHAR. These issues notwithstanding, the current scheme clearly provides a secure and rational basis for classifying and naming 5-HT receptors. The continued efforts of the SRNC are intended to encourage its further evolution towards the ultimate goal of a unitary classification for neurotransmitter/hormone receptors.” Thus, 5-HT6 and 5-HT7 receptors were accepted as fully characterised, whereas question marks remained and still remain for a few other receptors.

Also in 1996 and 1997, (20-22), we integrated new data on the 5-HT1B/1D receptors based on consolidated cloning and functional expression and eventually aligned the nomenclature to the human genome data: “The continuing rapid progress towards a complete database of structural information on the human genome creates a challenge of ensuring that current schemes for classifying and naming receptors and ion channels effectively integrate this information with functional data to provide unambiguous principles for classification. In this article, Paul Hartig and colleagues review the recent deliberations of the Serotonin Club Nomenclature Committee and outline a number of its recommendations aimed at encouraging consistency in current and future receptor nomenclature. Based on these principles, the present classification of 5-HT1B and 5-HT1D receptors is reconsidered, and a revised nomenclature for 5-HT1B, 5-HT1Dalpha and 5-HT1Dbeta receptor subtypes is suggested.” In essence, this paper was to clarify some ongoing complexities about 5-HT1B and 5-HT1D receptors as defined pharmacologically, and the increasing evidence coming from cloning/recombinant receptor studies which had identified 5-HT1Dalpha and 5-HT1Dbeta receptors. The rat 5-HT1B receptor had been cloned and displayed a typical rodent pharmacology (98). A canine clone called RDC4 (later named 5-HT1Dalpha) displayed a rather 5-HT1D type of pharmacological profile. To confuse matters, in humans there were two genes expressing 5-HT1D like pharmacology (99). The second gene was then named 5-HT1Dbeta. The rodent 5-HT1Dbeta receptor product expressed the typical 5-HT1B pharmacology whereas human version has a 5-HT1D like profile. It became then clear that rat 5-HT1B and human 5-HT1Dbeta were species homologues. A single amino acid difference was responsible for the change in pharmacological profile between rodents and the other species (100 103). Keep in mind that the 5-HT1B pharmacological profile was never reported in species other than rodents, and it had been suspected for quite some time that what was defined as human / porcine 5HT1D receptors were species homologues of the rodent 5-HT1B receptors as suggested by Hoyer and



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Middlemiss (50). Molecular biology had just confirmed this fact as illustrated by the differences in pharmacological profiles of the rodent and human version 5-HT1Dbeta receptor (e.g.5-HT1B vs 5-HT1D). Thus, 5-HT1Dbeta was renamed 5-HT1B, whereas 5-HT1Dalpha was then named 5-HT1D, since it had also a 5-HT1D pharmacological profile. The 5-HT1D receptor shows very little expression compared to 5-HT1B (77,78), and is very difficult to distinguish, as there are only a few selective drugs (104-105). The actual function of the 5-HT1D receptor still remains enigmatic. All triptans that are active in the acute treatment of migraine have very similar affinity and potency at 5-HT1B and 5-HT1D receptors; some of the triptans have affinity for the 5-HT1F receptor as well (106, 107). Given the cardiovascular liabilities of triptans and since 5-HT1B receptors are expressed in a number of vascular tissues, including coronary and pulmonary arteries, which is not the case for 5-HT1D receptors, it was anticipated that a 5-HT1D receptor agonist may be efficacious in the treatment of migraine with the advantage of being devoid of cardiovascular side effects. Unfortunately, this did not translate in the clinic, since the one 5-HT1D receptor agonist tested, PNU-142633 proved to be ineffective (108). However, the vascular liability of antimigraine drugs was to be re-addressed following the cloning of the 5-HT1F receptor (109) and the realisation that 5-HT1F receptor agonists are active in animals models of migraine (110, 111) and are effective in acute migraine (112), although their effects are thought to be neuronallymediated. Ultimately, lasmiditan (also known as COL-144) was developed and shown to be efficacious in acute migraine (113, 114), an NDA is expected in 2018.

Hoyer and Martin (21,22) further dealt with the realignment with the human Genome, recognising human species primacy, as made more explicit: “1), Human Species Primacy: establish operational profiles for all receptor subtypes in a family using, as a basis, the receptor genes present in the human genome. Endogenous receptor systems should be used where available, with data obtained in recombinant systems being identified in terms of the end-effect measured, host cell used and receptor expression density (5-HT1B/5-HT1D receptor subtypes…).  2). Use the same receptor subtype name for all species homologues of a gene (orthologous genes), but use brief letter prefixes to specify the species (e.g. h 5-HT2A, r 5-HT7) (for species abbreviations, see Vanhoutte et al., 1996). 3. Minimize changes to the historical nomenclature as much as possible so as to avoid confusion and facilitate the learning task for future researchers. An attempt should be made not to re-use names which previously received widespread use (e.g. 5-HT1C), and to avoid changes to widely used names unless a compelling reason is present.” Most of these recommendations have been amply accepted and followed across the receptor field. There will be exceptions and a proposal to rename somatostatin receptors based on similar principles was much less successful (115). Along the same lines, the renaming of the opiate receptors has not been readily accepted, for obvious reasons. What has been well known and accepted for decades should not been changed unless there are very compelling reasons. In the ion channel, the immunoreceptor or the kinome fields, where the complexity was extreme due to multiple names given to the same ligand or receptor or kinase, the renaming efforts have been much more successful, although this may still be work in progress. The complexities of the nomenclature system (e.g. for chemokines and their receptors) are exaggerated when multiple ligands may share a single receptor, and/or when a single ligand may target multiple receptors. In the following years, a number of updates have been published (23, 116, 117) taking into account new findings made regarding the molecular biology of 5-HT receptors, signal transduction diversity, new agonists and antagonists, and translational relevance: e.g. the detrimental effects of 5-HT2B receptors agonists such as fenfluramine, norfenfluramine, benfluorex, pergolide, cabergoline, or MDMA (see 118-123). 5-HT2B


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receptors agonists when given chronically, induce valvulopathies, pulmonary hypertension and have resulted in a significant number of deaths: thus most of these compounds were withdrawn from the market by the authorities in most countries. In the meantime, regular updates of the receptor nomenclature tables are to be found on the IUPHAR website and more recently in supplements of the British Journal of Pharmacology in printed or electronic edition every 2nd year (see 93-97). There are regular online updates on the websites performed in consultations with members of the 5-HT receptor nomenclature committee (see http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1.)

Future avenues and issues:

More recent highlights in the 5-HT field relate to the crystal structure of the 5-HT1B and 5-HT2B receptors (72, 73, 124). There is also a model of the 5-HT3 receptor, namely granisetron crystallized in complex with a model protein known as 5-HT Binding Protein, (5-HTBP, 125; see also 126). The crystal structure of the 5-HT3 receptor model confirms the pentameric nature of the receptor. Amongst the many exciting findings, it is interesting to note that the conformation of a number of agonists is different when bound to 5-HT1B or 5-HT2B receptors, in spite of very similar orthosteric binding sites. On another note, it appears that some ergolines (LSD, metergoline, DHE, ergotamine) bind to an accessory, possibly allosteric site, which is located outside of the orthosteric pocket. It also appears that some agonists induce different conformations of the ligand receptor complex that may translate into different signaling and/or translate into pathway selectivity. When extended to the 5-HT2A receptor, such findings may explain why LSD and related molecules have hallucinogenic effects, whereas other 5-HT2A receptor agonists are not hallucinogenic (127). It will be interesting to see whether such knowledge translates into better ligands by using structure-based molecular design (128). It has become clear, at least in the beta adrenergic receptor field that the concept of active and inactive states of the receptor molecule, whether in the presence or absence of ligand has become obsolete (129, 130). The receptors are much more diverse in their conformation than anticipated: almost every ligand appears to be able to form complexes with a given receptor that are somewhat different from any other ligand depending on the actual nature of the complex: receptor/Gprotein/accessory proteins/ arrestin/kinase… This invalidates the concept of “me too” ligands, in other words not all beta blockers or triptans or CGRPR antagonists are equal.

Work in progress in the 5-HT field, deals with outstanding issues such as naming splice variants that are different across species (e.g. for 5-HT4 or 5-HT7 receptors), or recognizing the functional value of editing variants of 5-HT2C receptors across species and diseases (131). A few other complicating factors, not specific to the 5-HT field, relate to receptor homomers or heteromers (132); the notion of constitutive activity and inverse agonism; receptor coupling to multiple G proteins as well as non G protein-mediated signaling; functional selectivity or biased agonism/antagonism; positive and negative allosteric modulators as allosteric binding sites probably exist for most receptors including 5HT; there even appears to be evidence for the existence of more than one orthosteric binding site for some GPCRs. Finally, there exists a whole range of accessory proteins which may modulate the function of various 5-HT receptors, whether at the surface of the cell or intracellularly (see e.g. 133-



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135). The 5-HT receptor nomenclature committee is taking care of these multiple aspects, which explains in part the very long time (>22 years), it has taken to produce an updated version of the 1994 Pharmacological Reviews paper, but we are getting closer. It has been a long journey, certainly worth the efforts of the many people involved over the years. It has helped to create order in a rather complex situation, especially at a time when the concepts of receptor families, subfamilies, subtypes, variants and species differences were not generally accepted by some “key opinion leaders”.

Supported by: NHMRC APP1105284 and APP1105332.

References:

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EVIDENCE FOR SPECIES-DIFFERENCES IN BRAIN SEROTONIN-2 RECEPTORS, European Journal of Pharmacology 106, 531-538. 40) Pazos, A., Hoyer, D., and Palacios, J. M. (1984) THE BINDING OF SEROTONERGIC LIGANDS TO THE PORCINE CHOROID-PLEXUS - CHARACTERIZATION OF A NEW TYPE OF SEROTONIN RECOGNITION SITE, European Journal of Pharmacology 106, 539-546. 41) Pazos, A., and Palacios, J. M. (1985) QUANTITATIVE AUTORADIOGRAPHIC MAPPING OF SEROTONIN RECEPTORS IN THE RAT-BRAIN .1. SEROTONIN-1 RECEPTORS, Brain Research 346, 205230..  42) Pazos, A., Cortes, R., and Palacios, J. M. (1985) QUANTITATIVE AUTORADIOGRAPHIC MAPPING OF SEROTONIN RECEPTORS IN THE RAT-BRAIN .2. SEROTONIN-2 RECEPTORS, Brain Research 346, 231249. 43) Pazos, A., Probst, A., and Palacios, J. M. (1987) SEROTONIN RECEPTORS IN THE HUMAN-BRAIN .3. AUTORADIOGRAPHIC MAPPING OF SEROTONIN-1 RECEPTORS, Neuroscience 21, 97-122.  44) Pazos, A., Probst, A., and Palacios, J. M. (1987) SEROTONIN RECEPTORS IN THE HUMAN-BRAIN .4. AUTORADIOGRAPHIC MAPPING OF SEROTONIN-2 RECEPTORS, Neuroscience 21, 123-139.  45) Hoyer, D., Pazos, A., Probst, A., and Palacios, J. M. (1986) SEROTONIN RECEPTORS IN THE HUMAN-BRAIN .1. CHARACTERIZATION AND AUTORADIOGRAPHIC LOCALIZATION OF 5-HT1A RECOGNITION SITES - APPARENT ABSENCE OF 5-HT1B RECOGNITION SITES, Brain Research 376, 8596. 46) Hoyer, D., Pazos, A., Probst, A., and Palacios, J. M. (1986) SEROTONIN RECEPTORS IN THE HUMAN-BRAIN .2. CHARACTERIZATION AND AUTORADIOGRAPHIC LOCALIZATION OF 5-HT1C AND 5HT2 RECOGNITION SITES, Brain Research 376, 97-107. 47) Hoyer, D., Srivatsa, S., Pazos, A., Engel, G., and Palacios, J. M. (1986) I-125 LSD LABELS 5-HT1C RECOGNITION SITES IN PIG CHOROID-PLEXUS MEMBRANES - COMPARISON WITH H-3 MESULERGINE AND H-3 5-HT BINDING, Neuroscience Letters 69, 269-274. 48) Hoyer, D., Waeber, C., Pazos, A., Probst, A., and Palacios, J. M. (1988) IDENTIFICATION OF A 5-HT1 RECOGNITION SITE IN HUMAN-BRAIN MEMBRANES DIFFERENT FROM 5-HT1A,5-HT1B AND 5-HT1C SITES, Neuroscience Letters 85, 357-362. 49) Waeber, C., Dietl, M. M., Hoyer, D., Probst, A., and Palacios, J. M. (1988) VISUALIZATION OF A NOVEL SEROTONIN RECOGNITION SITE (5-HT1D) IN THE HUMAN-BRAIN BY AUTORADIOGRAPHY, Neuroscience Letters 88, 11-16. 50) Hoyer, D., and Middlemiss, D. N. (1989) SPECIES-DIFFERENCES IN THE PHARMACOLOGY OF TERMINAL 5-HT AUTORECEPTORS IN MAMMALIAN BRAIN, Trends in Pharmacological Sciences 10, 130-132. 51) Waeber, C., Schoeffter, P., Palacios, J. M., and Hoyer, D. (1988) MOLECULAR PHARMACOLOGY OF 5-HT1D RECOGNITION SITES - RADIOLIGAND BINDING-STUDIES IN HUMAN, PIG AND CALF BRAIN MEMBRANES, Naunyn-Schmiedebergs Archives of Pharmacology 337, 595-601. 52) Waeber, C., Schoeffter, P., Palacios, J. M., and Hoyer, D. (1989) 5-HT1D RECEPTORS IN GUINEAPIG AND PIGEON BRAIN - RADIOLIGAND BINDING AND BIOCHEMICAL-STUDIES, NaunynSchmiedebergs Archives of Pharmacology 340, 479-485.



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126) Thompson, A. J., Lester, H. A., and Lummis, S. C. R. (2010) The structural basis of function in Cysloop receptors, Quarterly Reviews of Biophysics 43, 449-499.doi:10.1017/S0033583510000168. 127) Lee, H. M., and Roth, B. L. (2012) Hallucinogen actions on human brain revealed, Proceedings of the National Academy of Sciences of the United States of America 109, 1820-1821. 128) Shoichet, B. K., and Kobilka, B. K. (2012) Structure-based drug screening for G-protein-coupled receptors, Trends in Pharmacological Sciences 33, 268-272. 129) Kobilka, B. K. (2011) Structural insights into adrenergic receptor function and pharmacology, Trends in Pharmacological Sciences 32, 213-218. 130) Zocher, M., Fung, J. J., Kobilka, B. K., and Muller, D. J. (2012) Ligand-Specific Interactions Modulate Kinetic, Energetic, and Mechanical Properties of the Human beta(2) Adrenergic Receptor, Structure 20, 13911402. 131) Werry, T. D., Loiacono, R., Sexton, P. M., and Christopoulos, A. (2008) RNA editing of the serotonin 5HT(2C) receptor and its effects on cell signalling, pharmacology and brain function, Pharmacology & Therapeutics 119, 7-23. [PMID:18554725] 132) Xie, X. D., Lee, S. P., O'Dowd, B. F., and George, S. R. (1999) Serotonin 5-HT1B and 5-HT1D receptors form homodimers when expressed alone and heterodimers when co-expressed, Febs Letters 456, 63-67. [PMID:10452531] 133) Becamel, C., Alonso, G., Geleotti, N., Demey, E., Jouin, P., Ullmer, C., Dumuis, A., Bockaert, J., and Marin, P. (2002) Synaptic multiprotein complexes associated with 5-HT2C receptors: a proteomic approach, Embo Journal 21, 2332-2342. 134) Becamel, C., Figge, A., Poliak, S., Dumuis, A., Peles, E., Bockaert, J., Lubbert, H., and Ullmer, C. (2001) Interaction of serotonin 5-hydroxytryptamine type 2C receptors with PDZ10 of the multi-PDZ domain protein MUPP1, Journal of Biological Chemistry 276, 12974-12982. 135) Becamel, C., Gavarini, S., Chanrion, B., Alonso, G., Galeotti, N., Dumuis, A., Bockaert, J., and Marin, P. (2004) The serotonin 5-HT2A and 5-HT2C receptors interact with specific sets of PDZ proteins, Journal of Biological Chemistry 279, 20257-20266.


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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 1: Chronology of pharmacological advances in the 5-HT Field

Year

Advances

References

1930’s

Erspamer and colleagues describe enteramine as a gut constrictor

See 3

1938, 1943

LSD is synthesised and then rediscovered following Albert See 31 Hoffman’s famous bike trip back home

1948

Maurice Rapport synthesises and describes the vasoconstrictive 1,2 effects of serotonin (5-HT) with Page and colleagues

1953

Serotonin and enteramine represent the same entity

1954, 1957

Gaddum and Picarelli report on 2 serotonin receptors in the GP 4 ileum, called M and D

1977, 1979

Peroutka, Snyder, Fillion and colleagues report on S1 and S2 29, 34 receptors in the brain labelled by 5-HT and spiperone

1977

Middlemiss and colleagues report of the affinity of beta blockers 36 for 5-HT1 sites in the brain

1978

Leysen and colleagues report on the “narcoleptic receptor” as 5 labelled by antipsychotics.

1979

High affinity 5-HT binding linked to adenylate cyclase activity

1981

Nelson and colleagues discriminate 5-HT1A and 5-HT1B binding in 33 the brain

1981

Cyanopindolol is reported as a highly selective beta blocker and 10-12 radioligand

1982

Ketanserin described as a very potent and selective 5-HT2 receptor See 14, 40 antagonist and radioligand

19821983

8-OH-DPAT, the first selective 5-HT1A receptor agonist and 14, 37, 38, radioligand by Hjorth, Middlemiss, Hamon and colleagues

1983

Mesulergine, a dopamine antagonist is reported to label 5-HT2 32 receptors

1984

The 5-HT1C receptor is described in the brain in radioligand binding 39,40 and autoradiographic studies, species differences in 5-HT2 binding

19841987

Potent and selective 5-HT3 receptor antagonists reported, leading 26-28 to the later development of ondansetron, granisetron and tropisetron

19851986

A complete characterisation of 5-HT1A, 1B, 1C and 5-HT2 sites in 13,14, 39-46 rodent, mammal and human brain, using binding and autoradiography; apparent absence of 5-HT1B binding in porcine and human brain.

1986

5-HT1A receptor are positively coupled to adenylate cyclase (AC)


3

34

35


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 28

Year

Advances

References

1986

First nomenclature revision into 5-HT1-like (S1), 5-HT2 (S2, D) and 6 5-HT3 (M) receptors by Bradley and colleagues.

1986

5-HT1B autoreceptors described in the rat brain. 125

15

1986

[ I]ILSD labels 5-HT1C receptors

47

1988

5-HT 1A / 1B receptors negatively coupled to AC

8, 60, 61

19861989

Second messenger and structural consideration in receptor 79-82 characterisation; Is the 5-HT1C receptor a member of the 5-HT2 receptor family?

19871989

5-HT3 radioligand binding and autoradiography in neuroblastoma 57,58, 89-91 glioma cells, PNS and CNS

1988-

GR43175 (sumatriptan), a new 5-HT1-like receptor agonist for the 66-71 treatment of acute migraine

19881989

5-HT1D binding and distribution in non rodents; 5-HT1D receptors 48,49,51,52,59,60 negatively coupled to AC

1989

5-HT1D autoreceptors described in the rat brain

1989

Species differences in 5-HT autoreceptors, mediated by species 50 homologues

1989

GR43713 (sumatriptan), DHE and ergotamine suggested to 53,54 interact with 5-HT1D receptors

19891994

Similarities between 5-HT1B and 5-HT1D receptors in function, 52-56,59-62, 74distribution and transduction across species 78

19961998

Most triptans interact with 5-HT1B/1D and possibly 5-HT1F receptors

106,107

19971999

Pharmacological tools to separate 5-HT1B and 5-HT1D receptors

104,105

19972001

5-HT1F agonist efficacious in animal models and in acute migraine

110-114

2001

The selective 5-HT1D receptor agonist PNU142633 lacks efficacy in 108 acute migraine

20002011

5-HT2B receptor agonism, pulmonary hypertension and 119-123 valvulopathies: withdrawal of fenfluramine, norfenfluramine, benfluorex, pergolide and cabergoline.


16

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 2: Chronology of molecular biology and structure information of 5-HT receptors

Year

Advances

Refs, (see also PMID)

1986-1988

Cloning of the beta2 adrenoceptor, a homology 7-9, cloning leads to G21 an orphan, then cloning of the [PMID:1330647] beta1 adrenoceptor, recognition that G21 is the 5- [PMID:1610347] HT1A receptor

[PMID:1330647] [PMID:1348246]

1987-1989

Partial, then full sequence cloning of the 5-HT1C 83, 84, 87, receptor (5-HT2C) [PMID:1381232]

[PMID:1661811]

1988-

Cloning of the 5-HT2 receptor (5-HT2A)

1991-

Cloning of the 5-HT3 receptor (5-HT3A) and splice 92, [PMID:7565620] [PMID:7565620] variants [PMID:7683998] [PMID:1718042]

1991-1992

Cloning of the rat, mouse and human 5-HT1B 98-103,[PMID:1315531] receptor [PMID:1521164]

1992-

Cloning dog and human 5-HT1Dalpha/1Dbeta receptors, 99, [PMID:1565658] recognition that rat 5-HT1B and human 5-HT1Dbeta are species homologues

1992-

Cloning of the 5-ht1e receptor, not present in [PMID:1608964][PMID:1608964] rodents. [PMID:1513320]

1992-

Cloning of the 5-HT2B receptor (rat fundus)

88, [PMID:8078486] [PMID:8786115] [PMID:8143856][PMID:1426253] [PMID:1331748]

1993-

. Cloning of the 5-HT1F receptor

109, receptor [PMID:8380639] [PMID:9225282][PMID:1328180] [PMID:8384716]

1993-

. Cloning of the 5-HT5A receptor

[PMID:7682702] [PMID:7988681][PMID:8450829]

1993-

Cloning of the 5-ht5B receptor, not translated in [PMID:8450829] [PMID:9928243] humans

1993-

Cloning of the 5-HT6 receptor

[PMID:8522988][PMID:11406289] [PMID:7680751] [PMID:8389146]

1993-

Cloning of the 5-HT7 receptor and splice variants

[PMID:8394987][PMID:8398139] [PMID:8397408] [PMID:8394362]

1993

New 5-HT receptor nomenclature principles 17, 18 proposed: 4 receptor classes with subtypes, 5-HT1, 5HT2, 5-HT3, 5-HT4, agreeing that 5-HT5, 5-HT6 and 5HT7 receptors may exist; 5-HT1C renamed 5-HT2C, 5HT1C spot remains empty.

1994

Official IUPHAR 5-HT nomenclature adopted and 19 published, based on operational, transductional and sequence information. Distinction between genes and functional receptors, e.g. 5-ht1e, 5-ht1F, 5-ht5, 5-


86,87, [PMID:1330647] [PMID:1381232] [PMID:8087427]


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 28

Year

Advances Refs, (see also PMID) ht6 (sequence data, but no endogenous receptor data yet).

1995-

Cloning of the 5-HT4 receptor and splice variants

1996-1997

Reconciliation with the human genome, human 5- 20-22 HT1B and 5-HT1D pharmacological profile (with species variations), 5-HT4, 5-HT6, 5-HT7 recognised as functional entities

1997-

5-HT2C receptors are subject to RNA editing

1999

Cloning of 5-HT3B receptor and further subunits (5- [PMID:9950429][PMID:10521471] HT3C, 3D, 3E), functional expression of 5-HT3A/3B [PMID:10854267][PMID:14597179] heteromers [PMID:12801637] [PMID:17392525]

1999

5-HT1B and 1D receptors form heteromers

132

2000-

IUPHAR receptor compendium

93

2003-2008

Further refinements on 5-HT receptors

23, 117

2009

5-HT3 receptor heteropentamers, structure and [PMID:20409468] [PMID:18761359] function

2013

Crystal structure of the 5-HT1B and 5-HT2B receptors

[PMID:7796807][PMID:10646498] [PMID:9603189][PMID:9351641] [PMID:9349523][PMID:10220570] [PMID:9349523]

[PMID:11564657][PMID:9153397] [PMID:10432493][PMID:10991983] [PMID:10092629]

72,73, 124

2013, 2015, Guide to Pharmacology, constantly updated and 94-97 2017 published by IUPHAR and BJP every 2 years.


Page 27 of 28

[3H]5-HT % specific binding

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47


-log M [SDZ 21009] ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47

Triphasic competition of SDZ 21009, a beta blocker that recognises 5-HT1B sites with high affinity, 5-HT1A with intermediate affinity and 5-HT1C with low affinity. [3H]5-HT binding in rat cerebral cortex (from the author’s laboratory).


Page 28 of 28

5-HT Receptor Nomenclature: Naming Names, Does It Matter? A

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