5-HT Receptor Nomenclature: Naming names, does it matter? A

Review pubs.acs.org/chemneuro

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, California 92037, United States 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 (second 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-HT receptor nomenclature committee and the 5-HT community at large have helped to better define the pharmacology of the 5-HT receptor family. KEYWORDS: Serotonin, 5-HT, 5-hydroxytryptamine, receptors, serotonin club, nomenclature, IUPHAR

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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 1930s 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 and Picarelli4 in the guinea pig ileum, still quite an achievement, since most 5-HT receptors are expressed in the ileum. S1/S2 or 5-HT1/5-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 © 2017 American Chemical Society

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 characterization 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 realized 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 characterized.9 This illustrates the close relationship between 5-HT 1 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 Ph.D. Thesis subject: refs 10−12) was Special Issue: Serotonin Research 2016 Received: January 9, 2017 Accepted: March 7, 2017 Published: March 7, 2017 908

DOI: 10.1021/acschemneuro.7b00011 ACS Chem. Neurosci. 2017, 8, 908−919

ACS Chemical Neuroscience

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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. That is the beauty of Science, creating knowledge by having fun and making friends.

used to characterize 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.

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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 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 5-HT 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, 5HT2, 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 (5HTD), and 5-HT3 (5-HTM). There was acknowledgment 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, and 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, among others, to constitute the 5-HT nomenclature committee (to be led by Pat Humphrey). 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 were facilitated by advances in the molecular biology of GPCRs and ligandgated channels, such as 5-HT3 or GABAA. In addition, our medicinal chemists colleagues synthesized 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 intellectual property, not everything could be revealed, but it was agreed among 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 1996−1997, we recommended alignment with the human genome20−22 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 endeavor emerged multiple successful collaborations, between

HOYER ET AL. (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 time frame would be much more extensive, although some of us have pursued other interests. One of 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 and gastrointestinal, 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 review 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.

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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 Ph.D. Thesis (under the supervision of Profs. Jean-Claude 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 Ph.D. defense, 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 and Mike Tyers and colleagues in Glaxo/Ware were developing the first potent and selective 5HTM (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 909



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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 5-HT receptor agonists. A breakthrough was reached in 1983, when Middlemiss and Fozard37 described 8-OH-DPAT as a selective 5-HT1A ligand, and Michel Hamon and colleagues38 reported the selective labeling of 5-HT1A sites using [3H]8-OH-DPAT. In Basel, we were describing [3H]mesulergine binding in the choroid plexus39,40 that was displaced with high affinity by 5-HT, but not by ketanserin or spiperone, suggesting some form of 5HT1 binding. We further compared the features of [3H]mesulergine-labeled sites with those of classical 5-HT2 binding as labeled 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 5HT1B as evidenced in radioligand binding and autoradiographic studies performed in various species.39−46 5-HT1C sites had high affinity for 5-HT and LSD47 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 non-nervous 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., refs 48−51). Eventually, it turned out that only rat, mouse, and opossum had a 5-HT1 receptor with a classical 5-HT1B profile (see refs 13, 14, and 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 refs 48, 49, 51, and 59). The pharmacology of 5-HT1B and 5-HT1D binding

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 5HT1 and 5-HT2 receptors.29 Chema had completed a postdoc with Mike Kuhar, and introduced receptor autoradiography as a tool to discover, characterize, 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 postdoctoral work with Perry Molinoff (Chair of Pharmacology) at the University of Pennsylvania Medical School, where I worked on adrenoceptor desensitization 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 Sandoz in 1943 by Alfred Hoffman,31 as were many other compounds acting on 5-HT receptors, such as ergotamine, DHE, and the like. It was not known for quite some time which targets were engaged by these compounds, since 5-HT1,2 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 5-HT 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 chemotherapyinduced 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 promising27 but did not materialize, 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 M.D./Ph.D. 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 Snyder29 that [3H]5HT labeled 5-HT1 sites, that [3H]spiperone (and later [3H]ketanserin) labeled 5-HT2 sites, whereas [3H]LSD labeled both. However, David Nelson and colleagues during a sabbatical in Paris with Michel Hamon33 had already suggested that 5-HT1 binding was heterogeneous. Indeed, [3H]5-HT was 910



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Table 1. Chronology of Pharmacological Advances in the 5-HT Field year

advances

1930s 1938, 1943 1948 1953 1954, 1957 1977, 1979 1977 1978 1979 1981 1981 1982 1982−1983 1983 1984

1987−1989 19881988−1989

Erspamer and colleagues describe enteramine as a gut constrictor LSD is synthesized and then rediscovered following Albert Hoffman’s famous bike trip back home Maurice Rapport synthesizes and describes the vasoconstrictive effects of serotonin (5-HT) with Page and colleagues Serotonin and enteramine represent the same entity Gaddum and Picarelli report on 2 serotonin receptors in the GP ileum, called M and D Peroutka, Snyder, Fillion and colleagues report on S1 and S2 receptors in the brain labeled by 5-HT and spiperone Middlemiss and colleagues report of the affinity of beta blockers for 5-HT1 sites in the brain Leysen and colleagues report on the “narcoleptic receptor” as labeled by antipsychotics. High affinity 5-HT binding linked to adenylate cyclase activity Nelson and colleagues discriminate 5-HT1A and 5-HT1B binding in the brain Cyanopindolol is reported as a highly selective beta blocker and radioligand Ketanserin described as a very potent and selective 5-HT2 receptor antagonist and radioligand 8-OH-DPAT, the first selective 5-HT1A receptor agonist and radioligand by Hjorth, Middlemiss, Hamon and colleagues Mesulergine, a dopamine antagonist is reported to label 5-HT2 receptors The 5-HT1C receptor is described in the brain in radioligand binding and autoradiographic studies, species differences in 5-HT2 binding Potent and selective 5-HT3 receptor antagonists reported, leading to the later development of ondansetron, granisetron and tropisetron A complete characterization of 5-HT1A,1B,1C and 5-HT2 sites in rodent, mammal and human brain, using binding and autoradiography; apparent absence of 5-HT1B binding in porcine and human brain. 5-HT1A receptor are positively coupled to adenylate cyclase (AC) First nomenclature revision into 5-HT1-like (S1), 5-HT2 (S2, D) and 5-HT3 (M) receptors by Bradley and colleagues. 5-HT1B autoreceptors described in the rat brain. [125I]ILSD labels 5-HT1C receptors 5-HT 1A/1B receptors negatively coupled to AC Second messenger and structural consideration in receptor characterization; Is the 5-HT1C receptor a member of the 5-HT2 receptor family? 5-HT3 radioligand binding and autoradiography in neuroblastoma glioma cells, PNS and CNS GR43175 (sumatriptan), a new 5-HT1-like receptor agonist for the treatment of acute migraine 5-HT1D binding and distribution in nonrodents; 5-HT1D receptors negatively coupled to AC

1989 1989 1989 1989−1994

5-HT1D autoreceptors described in the rat brain Species differences in 5-HT autoreceptors, mediated by species homologues GR43715 (sumatriptan), DHE and ergotamine suggested to interact with 5-HT1D receptors Similarities between 5-HT1B and 5-HT1D receptors in function, distribution, and transduction across species

1996−1998 1997−1999 1997−2001 2001 2000−2011

Most triptans interact with 5-HT1B/1D and possibly 5-HT1F receptors Pharmacological tools to separate 5-HT1B and 5-HT1D receptors 5-HT1F agonist efficacious in animal models and in acute migraine The selective 5-HT1D receptor agonist PNU142633 lacks efficacy in acute migraine 5-HT2B receptor agonism, pulmonary hypertension and valvulopathies: withdrawal of fenfluramine, norfenfluramine, benfluorex, pergolide, and cabergoline.

1984−1987 1985−1986 1986 1986 1986 1986 1988 1986−1989

refs see ref 3 see ref 31 1, 2 3 4 29, 34 36 5 34 33 10−12 see refs 14, 40 14, 37, 38 32 39, 40 26−28 13, 14, 39−46 35 6 15 47 8, 60, 61 79−82 57, 58, 89−91 66−71 48, 49, 51, 52, 59, 60 16 50 53, 54 52−56, 59−62, 74−78 106, 107 104, 105 110−114 108 119−123

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 pharmacologies63−65 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 refs 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 agonist63 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 however that both 5-HT1B and 5HT1D receptors have a neuronal localization as well,74−78 including in the trigeminal ganglia.

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 characterized 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-HT 1B and 5-HT 1D were rather 911


912

1999 20002003−2008 2009 2013 2013, 2015, 2017

1999

1997-

1996−1997

1995-

1994

1993

1993-

199319931993-

1993-

1991−1992 199219921992-

1987−1989 19881991-

1986−1988

year

refs (see also PMID)

Cloning of the beta2 adrenoceptor, a homology cloning leads to G21 an orphan, then cloning of the beta1 adrenoceptor, recognition that 7−9, [PMID:1330647], [PMID:1330647], [PMID:1348246], G21 is the 5-HT1A receptor [PMID:1610347] Partial, then full sequence cloning of the 5-HT1C receptor (5-HT2C) 83, 84, 87, [PMID:1661811], [PMID:1381232] Cloning of the 5-HT2 receptor (5-HT2A) 86, 87, [PMID:1330647], [PMID:1381232], [PMID:8087427] Cloning of the 5-HT3 receptor (5-HT3A) and splice variants 92, [PMID:7565620], [PMID:7565620], [PMID:7683998], [PMID:1718042] Cloning of the rat, mouse and human 5-HT1B receptor 98−103, [PMID:1315531], [PMID:1521164] Cloning dog and human 5-HT1Dalpha/1Dbeta receptors, recognition that rat 5-HT1B and human 5-HT1Dbeta are species homologues 99, [PMID:1565658] Cloning of the 5-ht1e receptor, not present in rodents. [PMID:1608964], [PMID:1608964], [PMID:1513320] Cloning of the 5-HT2B receptor (rat fundus) 88, [PMID:8078486], [PMID:8786115], [PMID:8143856], [PMID:1426253], [PMID:1331748] Cloning of the 5-HT1F receptor 109, receptor [PMID:8380639], [PMID:9225282], [PMID:1328180], [PMID:8384716] Cloning of the 5-HT5A receptor [PMID:7682702], [PMID:7988681], [PMID:8450829] Cloning of the 5-ht5B receptor, not translated in humans [PMID:8450829] [PMID:9928243] Cloning of the 5-HT6 receptor [PMID:8522988], [PMID:11406289], [PMID:7680751], [PMID:8389146] Cloning of the 5-HT7 receptor and splice variants [PMID:8394987, ][PMID:8398139], [PMID:8397408], [PMID:8394362] New 5-HT receptor nomenclature principles proposed: 4 receptor classes with subtypes, 5-HT1, 5-HT2, 5-HT3, 5-HT4, agreeing that 5- 17, 18 HT5, 5-HT6 and 5-HT7 receptors may exist; 5-HT1C renamed 5-HT2C, 5-HT1C spot remains empty. Official IUPHAR 5-HT nomenclature adopted and published, based on operational, transductional and sequence information. Distinction 19 between genes and functional receptors, e.g. 5-ht1e, 5-ht1F, 5-ht5, 5-ht6 (sequence data, but no endogenous receptor data yet). Cloning of the 5-HT4 receptor and splice variants [PMID:7796807], [PMID:10646498], [PMID:9603189], [PMID:9351641], [PMID:9349523], [PMID:10220570], [PMID:9349523] Reconciliation with the human genome, human 5-HT1B and 5-HT1D pharmacological profile (with species variations), 5-HT4, 5-HT6, 5- 20−22 HT7 recognized as functional entities 5-HT2C receptors are subject to RNA editing [PMID:11564657], [PMID:9153397], [PMID:10432493], [PMID:10991983], [PMID:10092629] Cloning of 5-HT3B receptor and further subunits (5-HT3C,3D,3E), functional expression of 5-HT3A/3B heteromers [PMID:9950429], [PMID:10521471], [PMID:10854267], [PMID:14597179], [PMID:12801637], [PMID:17392525] 5-HT1B and 1D receptors form heteromers 132 IUPHAR receptor compendium 93 Further refinements on 5-HT receptors 23, 117 5-HT3 receptor heteropentamers, structure and function [PMID:20409468], [PMID:18761359] crystal structure of the 5-HT1B and 5-HT2B receptors 72, 73, 124 Guide to Pharmacology, constantly updated and published by IUPHAR and BJP every 2 years. 94−97

advances

Table 2. Chronology of Molecular Biology and Structure Information of 5-HT Receptors

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Review

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 paper19 went into much further detail 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 5HT receptor types and their characteristics. This derives f rom two main research approaches, operational pharmacology, using selective ligands (both agonists and antagonists), and, more recently, molecular biology. Although the scientif ic 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 classif ication. 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 classif ication, 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 identif ied 5-HT4 receptor almost undoubtedly represents a fourth 5HT 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 f ully characterized and classif ied to date (and, hence, named with conf idence) would seem to mediate the majority of the actions of 5HT throughout the mammalian body, not all receptors for 5-HT are f ully encompassed within our scheme of classif ication. These apparent anomalies must be recognized and need f urther 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 conf ident of the suitability of their appellations. Therefore, it is important to rationalise in concert all of the available data f rom studies involving both operational approaches of the classical pharmacological type and those f rom 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 on recombinant receptors that were much discussed and debated (see ref 21): “Information concerning the structural, operational and transductional characteristics of 5-HT receptors continues to increase at an incredible pace, challenging our ef forts to assimilate and organise it in a comprehensive manner. At the time of the Serotonin Satellite

On the other hand, it became evident that 5-HT2 receptors were coupled to PLC and calcium mobilization, 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 related81,82 and thus form a family distinct from 5-HT1. Based on this, the cloning of the 5-HT1C receptor83−85 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 ligandgated 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

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THE GENERATION OF THE CURRENT 5-HT RECEPTOR NOMENCLATURE The amount of information collected in the 1980−1990s 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 refs 94−97). Tables 1 and 2 attempt to give a chronological aspect of on how the 5-HT field evolved. Humphrey et al.17 set the scene by proposing up to seven 5HT receptor families with subfamilies for 5-HT1, 5-HT2, and 5HT3 receptors: this was based on operational or pharmacological (rank orders of potency for agonists and antagonists), transductional (preferred second messengers or ligand-gated 913



Review

meeting in Chicago (1994), the IUPHAR classif ication of receptors for 5-HT recognized four distinct receptor classes (5-HT1, 5-HT2, 5-HT3 and 5-HT4), comprising seven f ully characterized f unctional receptor subtypes and four recombinant receptors (5-HT1 Dalpha and 5-HT1Dbeta, 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 conf irmed the physiological importance of both 5-ht6 and 5-ht7 receptors so that in f uture schemes, these will be acknowledged as f ully characterized receptor classes. It is evident f rom 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 f undamental 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 classif ying and naming 5-HT receptors. The continued efforts of the SRNC are intended to encourage its f urther evolution towards the ultimate goal of a unitary classif ication for neurotransmitter/hormone receptors.” Thus, 5-HT6 and 5-HT7 receptors were accepted as fully characterized, 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 classif ying and naming receptors and ion channels effectively integrate this information with f unctional data to provide unambiguous principles for classif ication. 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 f uture receptor nomenclature. Based on these principles, the present classif ication of 5-HT1B and 5-HT1D receptors is reconsidered, and a revised nomenclature for 5-HT1B, 5-HT1 Dalpha 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-HT1 Dalpha 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-HT1 Dalpha) displayed a rather 5HT1D 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 5HT1B pharmacology whereas human version has a 5-HT1D like profile. It became then clear that rat 5-HT1B and human 5HT1Dbeta 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 5-HT1D receptors were species homologues of the rodent 5-HT 1B receptors as suggested by Hoyer and 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 5HT1 Dalpha 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 readdressed following the cloning of the 5-HT1F receptor109 and the realization that 5HT1F receptor agonists are active in animals models of migraine110,111 and are effective in acute migraine,112 although their effects are thought to be neuronally mediated. 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 Martin21,22 further dealt with the realignment with the human Genome, recognizing human species primacy, as made more explicit: “1), Human Species Primacy: establish operational prof iles 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 identif ied in terms of the end-ef fect 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 pref ixes to specif y the species (e.g., h 5-HT2A, r 5HT7) (for species abbreviations, see Vanhoutte et al., 1996). 3. Minimize changes to the historical nomenclature as much as possible so as to avoid conf usion and facilitate the learning task for f uture 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 wellknown 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 published23,116,117 taking into account new findings made regarding the molecular biology of 5-HT 914



Review

modulators as allosteric binding sites probably exist for most receptors including 5-HT; 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., refs 133−135). 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”.

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 refs 118−123). 5-HT2B 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 Web site and more recently in supplements of the British Journal of Pharmacology in printed or electronic edition every second year (see refs 93−97). There are regular online updates on the Web sites performed in consultations with members of the 5-HT receptor nomenclature committee (see http://www. guidetopharmacology.org/GRAC/ ObjectDisplayForward?objectId=1).

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AUTHOR INFORMATION

ORCID

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, ref 125; see also ref 126). The crystal structure of the 5-HT3 receptor model confirms the pentameric nature of the receptor. Among 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 5HT2B 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 structurebased 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/G-protein/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

Daniel Hoyer: 0000-0002-1405-7089 Notes

The author declares no competing financial interest.

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REFERENCES

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5-HT Receptor Nomenclature: Naming names, does it matter? A

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