5-HT receptor

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In the field of neurochemistry, 5-HT receptors are receptors for the neurotransmitter and peripheral signal mediator serotonin, also known as 5-hydroxytryptamine or 5-HT.^[1]^[2] 5-HT receptors are located on the cell membrane of nerve cells and other cell types including smooth muscle in animals, and mediate the effects of serotonin as the endogenous ligand and of a broad range of pharmaceutical and hallucinogenic drugs. 5-HT receptors affect the release and activity of other neurotransmitters such as glutamate, dopamine and GABA. 5-HT_2A receptors increase the activity of glutamate in many areas of the brain, while some other serotonin receptors have the effect of suppressing glutamate. Increased stimulation of 5-HT_2A receptors seem to oppose the therapeutic actions of increased stimulation of other serotonin receptors in anti-depressant and anxiolytic treatments.^[3]

Serotonin

1 Classification

1.1 Families 1.2 Specific proteins/genes

2 Therapeutic modulation 3 References 4 External links

[edit] Classification

With the exception of the 5-HT₃ receptor, a ligand gated ion channel, all other 5-HT receptors are G protein coupled seven transmembrane (or heptahelical) receptors that activate an intracellular second messenger cascade.

[edit] Families

Family Type Mechanism

5-HT₁ G_i/G_o coupled decreasing cellular levels of cAMP

5-HT₂ G_q/G₁₁ coupled increasing cellular levels of inositol trisphosphate (IP₃) and diacylglycerol (DAG)

5-HT₃ ligand-gated Na⁺ and K⁺ cation channel depolarizing plasma membrane

5-HT₄ G_s coupled increasing cellular levels of cAMP

5-HT_5A G protein coupled; the primary coupling appears to be through Gi/o inhibiting adenylate cyclase activity.^[4]

5-HT₆ G_s coupled increasing cellular levels of cAMP

5-HT₇ G_s coupled increasing cellular levels of cAMP

[edit] Specific proteins/genes

Within these general classes of 5-HT receptors, a number of specific types have been characterized:^[5]^[6]^[7]

Summary of characterized 5-HT receptors, with selected high affinity agonist and antagonist ligands

Receptor Gene Actions Agonists Antagonists

5-HT_1A HTR1A

CNS: neuronal inhibition, behavioural effects (sleep, feeding, thermoregulation, aggression, anxiety)

5-CT 8-OH-DPAT buspirone flesinoxan LSD MDMA (speculated)^[8] psilocin U-92016A^[9] vilazodone

ergotamine methiothepin pindolol robalzotan spiperone WAY-100135 WAY-100635^[10] yohimbine

5-HT_1B HTR1B

CNS: presynaptic inhibition, behavioural effects vascular: pulmonary vasoconstriction

ergotamine sumatriptan

metergoline methiothepin risperidone yohimbine

5-HT_1D HTR1D

CNS: locomotion, anxiety; vascular: cerebral vasoconstriction

5-(Nonyloxy)tryptamine^[11] sumatriptan

ergotamine metergoline methiothepin yohimbine

5-HT_1E HTR1E

BRL-54443 LSD (very low)

5-HT_1F HTR1F

BRL-54443 LY-334,370 LY-344,864

5-HT_2A HTR2A

CNS: neuronal excitation, behavioural effects, learning, anxiety smooth muscle: contraction, vasoconstriction / vasodilatation platelets: aggregation

Î±-methyl-5-HT AMT DMT LSD mescaline psilocin TCB-2

cyproheptadine ketanserin mirtazapine nefazodone pizotifen trazodone atypical antipsychotics

5-HT_2B HTR2B

stomach: contraction

Î±-methyl-5-HT DOI Fenfluramine LSD

yohimbine

5-HT_2C HTR2C

CNS: anxiety, choroid plexus: cerebrospinal fluid (CSF) secretion

Î±-methyl-5-HT DOI Lorcaserin LSD psilocin

agomelatine fluoxetine mesulergine methysergide^[12] SB-242,084

5-HT₃ HTR3A, HTR3B

CNS, PNS: neuronal excitation, anxiety, emesis

2-methyl-5-HT

alosetron memantine metoclopramide (high doses) mirtazapine ondansetron renzapride

5-HT₄ HTR4

GIT: gastrointestinal motility CNS: neuronal excitation, learning, memory

5-MT cisapride metoclopramide renzapride RS 67333 tegaserod

GR-113,808 Piboserod

5-HT_5A HTR5A

CNS (cortex, hippocampus, cerebellum): unknown

5-CT LSD^[4]

5-HT₆ HTR6

CNS: unknown

LSD

SB-271,046^[13]

5-HT₇ HTR7

CNS, GIT, blood vessels: unknown

5-CT LSD

methiothepin risperidone

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.

[edit] Therapeutic modulation

Various drugs are used to modulate the 5-HT system including some antidepressants, anxiolytics, antiemetics,antipsychotics and anti-migraine agents.^[14]

[edit] References

^ Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PP (1994). "International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin)". Pharmacol. Rev. 46 (2): 157â€“203. PMID 7938165. ^ Frazer A, Hensler JG (1999). "Chapter 13: Serotonin Receptors", in Siegel GJ, Agranoff BW, Albers RW, Fisher SK, Uhler MD, editors: Basic Neurochemistry: Molecular, Cellular, and Medical Aspects. Philadelphia: Lippincott-Raven, pages 263-292. ISBN 0-397-51820-X. Retrieved on 2008-04-11. ^ Marek GJ, Carpenter LL, McDougle CJ, Price LH (2003). "Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders". Neuropsychopharmacology 28 (2): 402â€“12. doi:10.1038/sj.npp.1300057. PMID 12589395. ^ ^a ^b Nelson DL (2004). "5-HT₅ receptors". Current drug targets. CNS and neurological disorders 3 (1): 53â€“8. PMID 14965244. ^ Glennon RA, Dukat M, Westkaemper RB (2000-01-01). "Serotonin Receptor Subtypes and Ligands". American College of Neurophyscopharmacology. Retrieved on 2008-04-11. ^ "5-Hydroxytryptamine Receptors". IUPHAR Receptor Database. International Union of Basic and Clinical Pharmacology. Retrieved on 2008-04-11. ^ WesoÅ‚owska A (2002). "In the search for selective ligands of 5-HT₅, 5-HT₆ and 5-HT₇ serotonin receptors". Polish Journal of Pharmacology 54 (4): 327â€“41. PMID 12523486. ^ Thompson MR, Callaghan PD, Hunt GE, Cornish JL, McGregor IS.. "A role for oxytocin and 5-HT(1A) receptors in the prosocial effects of 3,4 methylenedioxymethamphetamine ("ecstasy").". ^ McCall RB, Romero AG, Bienkowski MJ, Harris DW, McGuire JC, Piercey MF, Shuck ME, Smith MW, Svensson KA, Schreur PJ, et al. (1994). "Characterization of U-92016A as a selective, orally active, high intrinsic activity 5-hydroxytryptamine_1A agonist.". J. Pharmacol. Exp. Ther. 271 (2): 875-883. PMID 7965808. ^ Fornal CA, Metzler CW, Gallegos RA, Veasey SC, McCreary AC, Jacobs BL (1996). "WAY-100635, a potent and selective 5-hydroxytryptamine_1A antagonist, increases serotonergic neuronal activity in behaving cats: comparison with (S)-WAY-100135". J. Pharmacol. Exp. Ther. 278 (2): 752â€“62. PMID 8768728. ^ Glennon RA, Hong SS, Dukat M, Teitler M, Davis K (1994). "5-(Nonyloxy)tryptamine: a novel high-affinity 5-HT_1D beta serotonin receptor agonist". J. Med. Chem. 37 (18): 2828â€“30. doi:10.1021/jm00044a001. PMID 8071931. ^ Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 187 ^ "Target Schizophrenia - Possible future developments". The Association of the British Pharmaceutical Industry. Retrieved on 2008-04-11. ^ Nichols DE, Nichols CD (May 2008). "Serotonin receptors". Chem. Rev. 108 (5): 1614â€“41. doi:10.1021/cr078224o. PMID 18476671.