5-HT receptor

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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. 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.

Serotonin receptors are found in almost all animals and are even known to regulate longevity and behavioral aging in the primitive nematode, Caenorhabditis elegans.

Classification

5-hydroxytryptamine receptors or 5-HT receptors, or serotonin receptors are found in the central and peripheral nervous systems. 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.

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.	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. 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. The specific types have been characterized as follows:

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 File:7E2Y 5-HT1A receptor serotonin.png	HTR1A	Yes	Yes	No	No	No	No	Addiction Aggression Anxiety Appetite Autoreceptor Blood Pressure Cardiovascular Function Emesis Heart Rate Impulsivity Memory Mood Nausea Nociception Penile Erection Pupil Dilation Respiration Sexual Behavior Sleep Sociability Thermoregulation Vasoconstriction	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 (partial agonist) Vortioxetine (high-efficacy partial agonist) Ziprasidone (partial agonist, Ki = 3.4 nM) Methylphenidate (weak agonist)	BMY 7378 Cyanopindolol Iodocyanopindolol Lecozotan Methiothepin Methysergide 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 (agonist and antagonist)
5-HT1B	1992 – 6g79	HTR1B	Yes	Yes	No	No	No	No	Addiction Aggression Anxiety Autoreceptor Learning Locomotion Memory Mood Penile Erection Sexual Behavior Vasoconstriction	5-CT CGS-12066A CP-93,129 CP-94,253 Dihydroergotamine Eltoprazine Ergotamine Methysergide RU 24969 TFMPP Triptans (antimigraine) Zolmitriptan Eletriptan Sumatriptan Vortioxetine (partial agonist, Ki = 33 nM)	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 File:7E32 5-HT1D receptor.png	HTR1D	Yes	Yes	No	No	No	No	Anxiety Autoreceptor Locomotion Vasoconstriction	5-CT CP-135,807 Dihydroergotamine Ergotamine Methysergide Triptans (antimigraine) Almotriptan Eletriptan Frovatriptan Naratriptan Rizatriptan Sumatriptan Zolmitriptan Yohimbine	BRL-15572 GR-127,935 Ketanserin Metergoline Methiothepin Rauwolscine Ritanserin Vortioxetine (Ki = 54 nM) Ziprasidone	Migraines (e.g., triptans)
5-HT1E	1992 – 7e33 File:7E33 5-HT1E receptor.png	HTR1E	Yes	Yes	No	No	No	No		BRL-54443		None known
5-HT1F	1993 – 7exd File:7exd 5-HT1F receptor.png	HTR1F	No	Yes	No	No	No	No	Migraine	BRL-54443 Lasmiditan LY-334,370 Naratriptan Eletriptan		None known
5-HT1P	Not cloned		No	No	Yes	No	No	No	Peristalsis	5-OHIP 2-Methyl-5-HT 5-BOHIP	5-HTP-DP	None known
5-HT2A	1988	HTR2A	Yes	Yes	Yes	Yes	Yes	Yes	Addiction (potentially modulating) Anxiety Appetite Cognition Imagination Learning Memory Mood Perception Sexual Behavior Sleep Thermoregulation Vasoconstriction	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) Psilocin Psilocybin TFMPP (partial agonist or antagonist)	Atypical antipsychotics Clozapine Olanzapine Quetiapine Risperidone Ziprasidone Asenapine Amitriptyline Clomipramine Cyproheptadine Doxepin Eplivanserin Etoperidone Haloperidol Hydroxyzine Iloperidone Ketanserin (antihypertensive) 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	HTR2B	Yes	Yes	Yes	Yes	Yes	Yes	Anxiety Appetite Cardiovascular Function GI Motility Sleep Vasoconstriction	6-APB (full agonist) BW-723C86 Fenfluramine MDMA Norfenfluramine PNU-22394 (partial agonist) Ro60-0175 Methylphenidate (weak agonist)	Agomelatine Asenapine BZP Ketanserin Methysergide Ritanserin RS-127,445 Tegaserod Yohimbine	Migraines (antagonists)
5-HT2C	1988	HTR2C	Yes	Yes	Yes	Yes	Yes	Yes	Addiction (potentially modulating) Anxiety Appetite GI Motility Heteroreceptor for norepinephrine and dopamine Locomotion Mood Penile Erection Sexual Behavior Sleep Thermoregulation Vasoconstriction	2C-B (partial agonist) A-372,159 AL-38022A Aripiprazole Ergonovine Lorcaserin PNU-22394 (full agonist) Ro60-0175 TFMPP Trazodone (hypnotic) YM-348	Agomelatine (antidepressant) Amitriptyline Asenapine Clomipramine Clozapine (antipsychotic) Cyproheptadine Dimebolin Eltoprazine Etoperidone Fluoxetine Haloperidol Iloperidone Ketanserin (antihypertensive) Lisuride Methysergide 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	HTR3A HTR3B HTR3C HTR3D HTR3E	No	Yes	Yes	No	Yes	No	Addiction Anxiety Emesis GI Motility Learning Memory Nausea	2-Methyl-5-HT BZP Quipazine RS-56812	Alosetron Several antiemetics Dolasetron Ondansetron Granisetron Tropisetron Clozapine Memantine Metoclopramide Mianserin Mirtazapine Olanzapine Quetiapine Vortioxetine (Ki = 3.7 nM)	Antiemetic Antidepressant (e.g., mirtazpine) antipsychotic (e.g., olanzapine, quetiapine)
5-HT4	1995	HTR4	No	Yes	Yes	No	Yes	No	Anxiety Appetite GI Motility Learning Memory Mood Respiration	5-MT BIMU-8 Cinitapride Cisapride (gastroprokinetic) Dazopride Metoclopramide Mosapride Prucalopride RS-67333 Renzapride Tegaserod Zacopride	L-Lysine Piboserod	Gastroprokinetics (e.g., Tegaserod)
5-HT5A	1994 7UM4 7UM5 7UM6 7UM7	HTR5A	No	Yes	No	No	No	No	Autoreceptor Locomotion Sleep	5-CT Ergotamine Lisuride (partial) Methylergometrine (full) Valerenic Acid (partial agonist)	Asenapine Dimebolin Methiothepin Ritanserin SB-699,551 SB-699,551-A MS112	None thus far
5-HT5B	1993	HTR5BP	No	No	No	No	No	No	Functions in rodents, pseudogene in humans			None thus far
5-HT6	1993	HTR6	No	Yes	No	No	No	No	Anxiety Cognition Learning Memory Mood	EMD-386,088 EMDT WAY-181,187 WAY-208,466 E-6837 N-(inden-5-yl)imidazothiazole-5-sulfonamide (43)	Amitriptyline Aripiprazole Asenapine Clomipramine Clozapine Dimebolin EGIS-12233 Haloperidol Iloperidone MS-245 Olanzapine Ro04-6790 SB-258,585 SB-271,046 SB-357,134 SB-399,885	Antidepressant (antagonists and agonists) Anxiolytic (antagonists and agonist) Nootropic (antagonists) Anorectic (antagonists)
5-HT7	1993	HTR7	Yes	Yes	Yes	No	No	No	Anxiety Autoreceptor Memory Mood Respiration Sleep Thermoregulation Vasoconstriction Immunostimulation	5-CT 8-OH-DPAT Aripiprazole (partial agonist) 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)	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.

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. LSD (a psychedelic) is a 5-HT_1A, 5-HT_2A, 5-HT_2C, 5-HT_5A and 5-HT₆ agonist.

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.

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.

External links

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