5-HT receptor

File:4IAR.png

The 5-HT_1B receptor as an example of a metabotropic serotonin receptor. Its crystallographic structure in ribbon representation

5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in multiple tissues including the central and peripheral nervous systems.<ref name="pmid7938165">Template:Cite journal</ref><ref name="isbn0-397-51820-X">Template:Cite book</ref><ref>Template:Cite journal</ref> They mediate both excitatory and inhibitory neurotransmission. The serotonin (i.e., 5-hydroxytryptamine, hence "5-HT") receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand.

The serotonin receptors modulate the release of many neurotransmitters, including glutamate, GABA, dopamine, epinephrine / norepinephrine, and acetylcholine, as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticotropin, and substance P, among others. Serotonin receptors influence various biological and neurological processes such as aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation. They are the target of a variety of pharmaceutical and recreational drugs, including many antidepressants, antipsychotics, anorectics, antiemetics, gastroprokinetic agents, antimigraine agents, hallucinogens, and entactogens.<ref name="pmid18476671">Template:Cite journal</ref>

Serotonin receptors are found in almost all animals and are even known to regulate longevity and behavioral aging in the primitive nematode, Caenorhabditis elegans.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Classification

5-hydroxytryptamine receptors or 5-HT receptors, or serotonin receptors are found in the central and peripheral nervous systems.<ref name="pmid7938165"/><ref name="isbn0-397-51820-X"/> They can be divided into 7 families of G protein-coupled receptors which activate an intracellular second messenger cascade to produce an excitatory or inhibitory response. The exception to this is the 5-HT₃ receptor which is a ligand-gated ion channel. In 2014, a novel 5-HT receptor was isolated from the small white butterfly, Pieris rapae, and named pr5-HT₈. It does not occur in mammals and shares relatively low similarity to the known 5-HT receptor classes.<ref name="pmid25187179">Template:Cite journal</ref>

Families

Family	Type	Mechanism	Potential
5-HT1	Gi/Go-protein coupled.	Decreasing cellular levels of cAMP.	Inhibitory
5-HT2	Gq/G11-protein coupled.	Increasing cellular levels of IP3 and DAG.	Excitatory
5-HT3	Ligand-gated Na+ and K+ cation channel.	Depolarizing plasma membrane.	Excitatory
5-HT4	Gs-protein coupled.	Increasing cellular levels of cAMP.	Excitatory
5-HT5	Gi/Go-protein coupled.<ref name="pmid9865521">Template:Cite journal</ref>	Decreasing cellular levels of cAMP.	Inhibitory
5-HT6	Gs-protein coupled.	Increasing cellular levels of cAMP.	Excitatory
5-HT7	Gs-protein coupled.	Increasing cellular levels of cAMP.	Excitatory

Subtypes

The 7 general serotonin receptor classes include a total of 14 known serotonin receptors.<ref name="NHM-14 receptors">Template:Cite book</ref> The 15th receptor 5-HT_1P has been distinguished on the basis of functional and radioligand binding studies, its existence has never been definitely affirmed or refuted.<ref>Template:Cite book</ref><ref name=":1">Template:Cite journal</ref> The specific types have been characterized as follows:<ref name="urlSerotonin Receptor Subtypes and Ligands">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="urlIUPHAR DATABASE | 5-HYDROXYTRYPTAMINE RECEPTORS">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Wesolowska_2002">Template:Cite journal</ref>

Information on serotonin receptors (human isoforms if nothing else is stated)
Receptor	First cloned – PDB entries	Gene(s)	Distribution						Function	Agonists	Antagonists	Uses of drugs that act on this receptor
			Blood vessels	CNS	GI Tract	Platelets	PNS	Smooth Muscle
5-HT1A	1987 – 7e2x 7e2y 7e2z	Template:Gene	Template:Yes	Template:Yes	Template:No	Template:No	Template:No	Template:No	Addiction<ref name="pmid7862892">Template:Cite journal</ref><ref name="pmid17316955">Template:Cite journal</ref><ref name="pmid15713268">Template:Cite journal</ref> Aggression<ref name="pmid16310183">Template:Cite journal</ref> Anxiety<ref name="pmid9724773">Template:Cite journal</ref> Appetite<ref name="pmid17609739">Template:Cite journal</ref> Autoreceptor Blood Pressure<ref name="pmid2842163">Template:Cite journal</ref><ref name="pmid18667366">Template:Cite journal</ref> Cardiovascular Function<ref name="pmid15802554">Template:Cite journal</ref> Emesis<ref name="pmid8013549">Template:Cite journal</ref> Heart Rate<ref name="pmid2842163"/><ref name="pmid18667366"/> Impulsivity<ref name="pmid15688093">Template:Cite journal</ref> Memory<ref name="pmid18394726">Template:Cite journal</ref><ref name="pmid12562581">Template:Cite journal</ref> Mood<ref name="pmid2883013">Template:Cite journal</ref> Nausea<ref name="pmid8013549"/> Nociception<ref name="pmid12595749">Template:Cite journal</ref> Penile Erection<ref name="pmid9085055">Template:Cite journal</ref> Pupil Dilation<ref name="pmid8982715">Template:Cite journal</ref> Respiration<ref name="pmid16166206">Template:Cite journal</ref> Sexual Behavior<ref name="pmid11965359">Template:Cite journal</ref> Sleep<ref name="pmid10607047">Template:Cite journal</ref> Sociability<ref name="pmid17383105">Template:Cite journal</ref> Thermoregulation<ref name="pmid2951611">Template:Cite journal</ref> Vasoconstriction<ref name="pmid16455061">Template:Cite journal</ref>	Selective (for 5-HT1A over other 5-HT receptors) Vilazodone (Viibryd) F-15,599 (research compound, highly potent and selective for 5-HT1A) Flesinoxan (potent, EC50 = 24 nM) Gepirone (partial agonist, Ki = 70 nM) Haloperidol Ipsapirone (partial agonist, Ki = 12.1 nM) Quetiapine Trazodone (SARI, selective in the sense that on all other 5-HT receptors it acts as either an antagonist or has no action. Kd = 78 nM) Yohimbine (unselective partial agonist) Tandospirone (potent and selective partial agonist) Nonselective 5-CT (potent – Ki = 250 ± 50 pM) 8-OH-DPAT (potent) Aripiprazole (atypical antipsychotic) Asenapine (atypical antipsychotic) Buspirone<ref name=pharmamotion>Pharmacology Corner > Serotonin (5-HT): receptors, agonists and antagonists By Flavio Guzmán, M.D. on 9/08/09</ref> (partial agonist) Vortioxetine (high-efficacy partial agonist)<ref name="vortioxetine">"BRINTELLIX (vortioxetine) tablets for oral use. Full Prescribing Information, Section 12.2 (Pharmacodynamics)." Takeda Pharmaceuticals America Inc. and Lundbeck, 2013. Revised September 2013. [1] Template:Webarchive</ref> Ziprasidone (partial agonist, Ki = 3.4 nM) Methylphenidate (weak agonist)	BMY 7378 Cyanopindolol Iodocyanopindolol Lecozotan Methiothepin Methysergide<ref>Template:Cite journal</ref> NAN-190 Nebivolol Nefazodone WAY-100,135 WAY-100,635 Mefway	Analgesics (agonists) Antidepressants (post-synaptic receptor agonists and pre-synaptic autoreceptor antagonists serve as antidepressants) Anxiolytics<ref name="pmid9784072">Template:Cite journal</ref> (agonist and antagonist)
5-HT1B	1992 – 6g79	Template:Gene	Template:Yes	Template:Yes	Template:No	Template:No	Template:No	Template:No	Addiction<ref name="pmid10027505">Template:Cite journal</ref> Aggression<ref name="pmid16310183"/> Anxiety<ref name="pmid15720791">Template:Cite journal</ref><ref name="pmid11888549">Template:Cite journal</ref><ref name="pmid15577451">Template:Cite journal</ref> Autoreceptor Learning<ref name="pmid18394658">Template:Cite journal</ref> Locomotion<ref name="pmid10454466">Template:Cite journal</ref> Memory<ref name="pmid18394658"/> Mood<ref name="pmid15577451"/> Penile Erection<ref name="pmid9085055"/> Sexual Behavior<ref name="pmid11965359"/> Vasoconstriction	5-CT CGS-12066A CP-93,129 CP-94,253 Dihydroergotamine Eltoprazine Ergotamine Methysergide RU 24969 TFMPP Triptans<ref name=pharmamotion/> (antimigraine<ref name=pharmamotion/>) Zolmitriptan Eletriptan Sumatriptan Vortioxetine (partial agonist, Ki = 33 nM)<ref name="vortioxetine" />	Alprenolol AR-A000002 Asenapine Cyanopindolol GR-127,935 Iodocyanopindolol Isamoltane Metergoline Methiothepin Oxprenolol Pindolol Propranolol SB-216,641 Yohimbine	Migraines (e.g., triptans)
5-HT1D	1991 – 7e32	Template:Gene	Template:Yes	Template:Yes	Template:No	Template:No	Template:No	Template:No	Anxiety<ref name="pmid15820416">Template:Cite journal</ref><ref name="pmid8736648">Template:Cite journal</ref> Autoreceptor Locomotion<ref name="pmid10454466"/> Vasoconstriction	5-CT CP-135,807 Dihydroergotamine Ergotamine Methysergide Triptans<ref name=pharmamotion/> (antimigraine<ref name=pharmamotion/>) Almotriptan Eletriptan Frovatriptan Naratriptan Rizatriptan Sumatriptan Zolmitriptan Yohimbine	BRL-15572 GR-127,935 Ketanserin Metergoline Methiothepin Rauwolscine Ritanserin Vortioxetine (Ki = 54 nM)<ref name="vortioxetine" /> Ziprasidone	Migraines (e.g., triptans)
5-HT1E	1992 – 7e33	Template:Gene	Template:Yes	Template:Yes	Template:No	Template:No	Template:No	Template:No		BRL-54443		None known
5-HT1F	1993 – 7exd	Template:Gene	Template:No	Template:Yes	Template:No	Template:No	Template:No	Template:No	Migraine	BRL-54443 Lasmiditan LY-334,370 Naratriptan Eletriptan		None known
5-HT1P	Not cloned		Template:No	Template:No	Template:Yes	Template:No	Template:No	Template:No	Peristalsis<ref name=":1" /><ref>Template:Cite journal</ref>	5-OHIP<ref name=":1" /><ref>Template:Cite journal</ref> 2-Methyl-5-HT<ref>Template:Cite journal</ref> 5-BOHIP<ref>Template:Cite journal</ref>	5-HTP-DP<ref name=":1" />	None known
5-HT2A	1988	Template:Gene	Template:Yes	Template:Yes	Template:Yes	Template:Yes	Template:Yes	Template:Yes	Addiction (potentially modulating)<ref name="Bubar">Template:Cite journal</ref> Anxiety<ref name="pmid9539263">Template:Cite journal</ref> Appetite Cognition Imagination Learning Memory Mood Perception Sexual Behavior<ref name="pmid12097814">Template:Cite journal</ref> Sleep<ref name="pmid16339018">Template:Cite journal</ref> Thermoregulation<ref name="pmid9106912">Template:Cite journal</ref> Vasoconstriction<ref name="pmid12654345">Template:Cite journal</ref>	25I-NBOMe (Full agonist) 2C-B 2C-I 5-MeO-DMT Aripiprazole (very weak partial agonist or antagonist) BZP Bufotenin DMT DOM Ergonovine Lisuride LSD Mescaline PNU-22394 (partial agonist)<ref name="McCall2001">Template:Cite conference</ref><ref name="pmid19029184">Template:Cite journal</ref><ref name="Jensen2013">Template:Cite journal</ref> Psilocin Psilocybin TFMPP (partial agonist or antagonist)	Atypical antipsychotics Clozapine<ref name="pharmamotion" /> Olanzapine Quetiapine Risperidone Ziprasidone Asenapine Amitriptyline Clomipramine Cyproheptadine Doxepin Eplivanserin Etoperidone Haloperidol Hydroxyzine Iloperidone Ketanserin<ref name=pharmamotion/> (antihypertensive<ref name=pharmamotion/>) Methysergide Mianserin Mirtazapine Nefazodone Pimavanserin Pizotifen Ritanserin Trazodone Yohimbine	Atypical antipsychotics (antagonist) Psychedelics (agonists) NaSSAs (antidepressants and anxiolytics; they serve as antagonists at this site) Treating serotonin syndrome (antagonists; e.g., cyproheptadine) Sleeping aid (antagonists; e.g., trazodone)
5-HT2B	1992	Template:Gene	Template:Yes	Template:Yes	Template:Yes	Template:Yes	Template:Yes	Template:Yes	Anxiety<ref name="pmid8730737">Template:Cite journal</ref><ref name="pmid9225285">Template:Cite journal</ref><ref name="pmid9886683">Template:Cite journal</ref> Appetite<ref name="pmid9144661">Template:Cite journal</ref> Cardiovascular Function GI Motility<ref name="pmid11877320">Template:Cite journal</ref> Sleep<ref name="pmid16339018"/> Vasoconstriction	6-APB (full agonist) BW-723C86 Fenfluramine MDMA Norfenfluramine PNU-22394 (partial agonist)<ref name="McCall2001" /><ref name="pmid19029184" /><ref name="Jensen2013" /> Ro60-0175 Methylphenidate (weak agonist)	Agomelatine Asenapine BZP Ketanserin Methysergide Ritanserin RS-127,445 Tegaserod Yohimbine	Migraines (antagonists)
5-HT2C	1988	Template:Gene	Template:Yes	Template:Yes	Template:Yes	Template:Yes	Template:Yes	Template:Yes	Addiction (potentially modulating)<ref name="Bubar"/> Anxiety<ref name="pmid9225286">Template:Cite journal</ref><ref name="pmid15289999">Template:Cite journal</ref><ref name="pmid18523738">Template:Cite journal</ref> Appetite GI Motility<ref name="pmid19058784">Template:Cite journal</ref> Heteroreceptor for norepinephrine and dopamine Locomotion Mood<ref name="pmid15289999"/><ref name="pmid18523738"/> Penile Erection<ref name="pmid9151932">Template:Cite journal</ref><ref name="pmid8001637">Template:Cite journal</ref> Sexual Behavior<ref name="pmid12097814"/> Sleep<ref name="pmid12431861">Template:Cite journal</ref> Thermoregulation<ref name="pmid9106912"/> Vasoconstriction	2C-B (partial agonist)<ref>Template:Cite journal</ref> A-372,159 AL-38022A Aripiprazole Ergonovine Lorcaserin PNU-22394 (full agonist)<ref name="McCall2001" /><ref name="pmid19029184" /><ref name="Jensen2013" /> Ro60-0175 TFMPP Trazodone<ref name=pharmamotion/> (hypnotic<ref name=pharmamotion/>) YM-348	Agomelatine<ref name=pharmamotion/> (antidepressant<ref name=pharmamotion/>) Amitriptyline Asenapine Clomipramine Clozapine<ref name=pharmamotion/> (antipsychotic<ref name=pharmamotion/>) Cyproheptadine Dimebolin Eltoprazine Etoperidone Fluoxetine Haloperidol Iloperidone Ketanserin<ref name=pharmamotion/> (antihypertensive<ref name=pharmamotion/>) Lisuride Methysergide<ref name=Rang187>Template:Cite book Page 187</ref> Mianserin Mirtazapine Nefazodone Olanzapine Paroxetine Quetiapine Risperidone Ritanserin SB-242084 Tramadol Trazodone Ziprasidone	Antidepressant (antagonists; e.g., agomelatine, fluoxetine, mirtazapine) Orexigenic (e.g., mirtazapine, clozapine and olanzapine; antagonists) Anorectic (Lorcaserin; agonist) Antipsychotic (Vabicaserin; agonists)
5-HT3	1993	Template:Gene Template:Gene Template:Gene Template:Gene Template:Gene	Template:No	Template:Yes	Template:Yes	Template:No	Template:Yes	Template:No	Addiction Anxiety Emesis GI Motility<ref>Template:Cite journal</ref> Learning<ref name="pmid8115433">Template:Cite journal</ref> Memory<ref name="pmid8115433"/> Nausea	2-Methyl-5-HT BZP Quipazine RS-56812	Alosetron Several antiemetics<ref name=pharmamotion/> Dolasetron Ondansetron<ref name=pharmamotion/> Granisetron Tropisetron Clozapine Memantine Metoclopramide Mianserin Mirtazapine Olanzapine Quetiapine Vortioxetine (Ki = 3.7 nM)<ref name="vortioxetine" />	Antiemetic Antidepressant (e.g., mirtazpine) antipsychotic (e.g., olanzapine, quetiapine)
5-HT4	1995	Template:Gene	Template:No	Template:Yes	Template:Yes	Template:No	Template:Yes	Template:No	Anxiety<ref name="pmid14676321">Template:Cite journal</ref><ref name="pmid9225297">Template:Cite journal</ref> Appetite<ref name="pmid17913892">Template:Cite journal</ref><ref name="pmid15146954">Template:Cite journal</ref> GI Motility Learning<ref name="Meneses A, Hong E 1997 347–51">Template:Cite journal</ref><ref name="pmid9225295">Template:Cite journal</ref> Memory<ref name="Meneses A, Hong E 1997 347–51"/><ref name="pmid9225295"/><ref name="pmid9732367">Template:Cite journal</ref> Mood<ref name="pmid17785179">Template:Cite journal</ref><ref name="pmid17785173">Template:Cite journal</ref> Respiration<ref name="Manzke2003">Template:Cite journal</ref>	5-MT BIMU-8 Cinitapride Cisapride<ref name=pharmamotion/> (gastroprokinetic) Dazopride Metoclopramide Mosapride Prucalopride RS-67333 Renzapride Tegaserod Zacopride	L-Lysine<ref name="pmid14676321"/> Piboserod	Gastroprokinetics (e.g., Tegaserod)
5-HT5A	1994 7UM4 7UM5 7UM6 7UM7	Template:Gene	Template:No	Template:Yes	Template:No	Template:No	Template:No	Template:No	Autoreceptor Locomotion<ref name="pmid14965244">Template:Cite journal</ref> Sleep<ref name="pmid15921820">Template:Cite journal</ref>	5-CT Ergotamine Lisuride (partial)<ref name=":0">Template:Cite journal</ref> Methylergometrine (full)<ref name=":0" /> Valerenic Acid (partial agonist)<ref name="pmid15921820"/>	Asenapine Dimebolin Methiothepin Ritanserin SB-699,551 SB-699,551-A MS112<ref name=":0" />	None thus far
5-HT5B	1993	Template:Gene	Template:No	Template:No	Template:No	Template:No	Template:No	Template:No	Functions in rodents, pseudogene in humans			None thus far
5-HT6	1993	Template:Gene	Template:No	Template:Yes	Template:No	Template:No	Template:No	Template:No	Anxiety<ref name="pmid18096153">Template:Cite journal</ref><ref name="pmid17320917">Template:Cite journal</ref> Cognition<ref name="pmid17069795">Template:Cite journal</ref> Learning<ref name="pmid15964617">Template:Cite journal</ref> Memory<ref name="pmid15964617"/> Mood<ref name="pmid17320917"/><ref name="pmid18234190">Template:Cite journal</ref>	EMD-386,088 EMDT WAY-181,187 WAY-208,466 E-6837 N-(inden-5-yl)imidazothiazole-5-sulfonamide (43)<ref name="pmid19159187">Template:Cite journal</ref>	Amitriptyline Aripiprazole Asenapine Clomipramine Clozapine Dimebolin EGIS-12233 Haloperidol Iloperidone MS-245 Olanzapine Ro04-6790 SB-258,585 SB-271,046<ref name="abpi2003">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref> SB-357,134 SB-399,885	Antidepressant (antagonists and agonists) Anxiolytic (antagonists and agonist) Nootropic (antagonists) Anorectic (antagonists)
5-HT7	1993	Template:Gene	Template:Yes	Template:Yes	Template:Yes	Template:No	Template:No	Template:No	Anxiety<ref name="pmid16018977">Template:Cite journal</ref><ref name="pmid16828124">Template:Cite journal</ref> Autoreceptor Memory<ref name="pmid18308404">Template:Cite journal</ref><ref name="pmid18570192">Template:Cite journal</ref> Mood<ref name="pmid16018977"/><ref name="pmid16828124"/> Respiration<ref name="pmid16166206"/><ref name="pmid17314195">Template:Cite journal</ref> Sleep<ref name="pmid16018977"/><ref name="pmid17314195"/><ref name="pmid12812993">Template:Cite journal</ref> Thermoregulation Vasoconstriction Immunostimulation<ref>Template:Cite journal</ref>	5-CT 8-OH-DPAT Aripiprazole (partial agonist)<ref>Davies MA, Sheffler DJ, Roth BL. Aripiprazole: A Novel Atypical Antipsychotic Drug With a Uniquely Robust Pharmacology. CNS Drug Reviews [Internet]. 2004 [cited 2013 Aug 4];10(4):317–36. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1527-3458.2004.tb00030.x/pdf</ref> AS-19 E-55888	Amitriptyline Asenapine Clomipramine Clozapine EGIS-12233 Haloperidol Iloperidone Imipramine Ketanserin Mirtazapine Olanzapine RA-7 Ritanserin Risperidone SB-269,970 Vortioxetine (Ki = 19 nM)<ref name="vortioxetine" />	Antidepressant (antagonists) Anxiolytics (antagonists) Nootropic (antagonists)

Note that there is no 5-HT_1C receptor since, after the receptor was cloned and further characterized, it was found to have more in common with the 5-HT₂ family of receptors and was redesignated as the 5-HT_2C receptor.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Very nonselective agonists of 5-HT receptor subtypes include ergotamine (an antimigraine), which activates 5-HT_1A, 5-HT_1D, 5-HT_1B, D₂ and norepinephrine receptors.<ref name=pharmamotion/> LSD (a psychedelic) is a 5-HT_1A, 5-HT_2A, 5-HT_2C, 5-HT_5A and 5-HT₆ agonist.<ref name=pharmamotion/>

Expression patterns

The genes coding for serotonin receptors are expressed across the mammalian brain. Genes coding for different receptors types follow different developmental curves. Specifically, there is a developmental increase of HTR5A expression in several subregions of the human cortex, paralleled by a decreased expression of HTR1A from the embryonic period to the post-natal one. <ref name="pmid26636753">Template:Cite journal</ref>

5-HT₁-like

A number of receptors were classed as "5-HT₁-like" - by 1998 it was being argued that, since these receptors were "a heterogeneous population of 5-HT1B, 5-HT1D and 5-HT7" receptors the classification was redundant.<ref>Template:Cite journal</ref>

External links

• Template:MeshName
• {{#invoke:citation/CS1|citation

|CitationClass=web }}

• {{#invoke:citation/CS1|citation

|CitationClass=web }}

• Template:Cite journal