Jump to content

5-HT2B receptor

From Wikipedia, the free encyclopedia
HTR2B
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesHTR2B, 5-HT(2B), 5-HT2B, 5-HT-2B, 5-hydroxytryptamine receptor 2B
External IDsOMIM: 601122; MGI: 109323; HomoloGene: 55492; GeneCards: HTR2B; OMA:HTR2B - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3357

15559

Ensembl

ENSG00000135914

ENSMUSG00000026228

UniProt

P41595

Q02152

RefSeq (mRNA)

NM_000867
NM_001320758

NM_008311

RefSeq (protein)

NP_000858
NP_001307687

NP_032337

Location (UCSC)Chr 2: 231.11 – 231.13 MbChr 1: 86.03 – 86.04 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

5-Hydroxytryptamine receptor 2B (5-HT2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2B gene.[5][6] 5-HT2B is a member of the 5-HT2 receptor family that binds the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). Like all 5-HT2 receptors, the 5-HT2B receptor is Gq/G11-protein coupled, leading to downstream activation of phospholipase C.

Tissue distribution and function[edit]

First discovered in the stomach of rats, 5-HT2B was challenging to characterize initially because of its structural similarity to the other 5-HT2 receptors, particularly 5-HT2C.[7] The 5-HT2 receptors (of which the 5-HT2B receptor is a subtype) mediate many of the central and peripheral physiologic functions of serotonin. Cardiovascular effects include contraction of blood vessels and shape changes in platelets; central nervous system (CNS) effects include neuronal sensitization to tactile stimuli and mediation of some of the effects of hallucinogenic substituted amphetamines. The 5-HT2B receptor is expressed in several areas of the CNS, including the dorsal hypothalamus, frontal cortex, medial amygdala, and meninges.[8] However, its most important role is in the peripheral nervous system (PNS) where it maintains the viability and efficiency of the cardiac valve leaflets.[9]

The 5-HT2B receptor subtype is involved in:

  • CNS: inhibition of serotonin and dopamine uptake, behavioral effects[10]
  • Vascular: pulmonary vasoconstriction[11]
  • Cardiac: The 5-HT2B receptor regulates cardiac structure and functions, as demonstrated by the abnormal cardiac development observed in 5-HT2B receptor null mice.[12] Excessive stimulation of this receptor causes pathological proliferation of cardiac valve fibroblasts,[13] with chronic overstimulation leading to valvulopathy.[14][15] These receptors are also overexpressed in human failing heart and antagonists of 5-HT2B receptors were discovered to prevent both angiotensin II or beta-adrenergic agonist-induced pathological cardiac hypertrophy in mouse.[16][17][18]
  • Serotonin transporter: 5-HT2B receptors regulate serotonin release via the serotonin transporter, and are important both to normal physiological regulation of serotonin levels in blood plasma,[19] and with the abnormal acute serotonin release produced by drugs such as MDMA.[10] Surprisingly, however, 5-HT2B receptor activation appears to be protective against the development of serotonin syndrome following elevated extracellular serotonin levels,[20] despite its role in modulating serotonin release.

Clinical significance[edit]

5-HT2B receptors have been strongly implicated in causing drug-induced valvular heart disease.[21][22][23] The Fen-Phen scandal in the 80s and 90s revealed the cardiotoxic effects of 5-HT2B stimulation.[24] Today, 5-HT2B agonism is considered a toxicity signal precluding further clinical development of a compound.[25]

Ligands[edit]

The structure of the 5-HT2B receptor was resolved in a complex with the valvulopathogenic drug ergotamine.[26] As of 2009, few highly selective 5-HT2B receptor ligands have been discovered, although numerous potent non-selective compounds are known, particularly agents with concomitant 5-HT2C binding. Research in this area has been limited due to the cardiotoxicity of 5-HT2B agonists, and the lack of clear therapeutic application for 5-HT2B antagonists, but there is still a need for selective ligands for scientific research.[27]

Agonists[edit]

Selective
Non-selective

Antagonists[edit]

Possible applications[edit]

5-HT2B antagonists have previously been proposed as treatment for migraine headaches, and RS-127,445 was trialled in humans up to Phase I for this indication, but development was not continued.[47] More recent research has focused on possible application of 5-HT2B antagonists as treatments for chronic heart disease.[48][49] Research claims serotonin 5-HT2B receptors have effect on liver regeneration.[50] Antagonism of 5-HT2B may attenuate fibrogenesis and improve liver function in disease models in which fibrosis is pre-established and progressive.

See also[edit]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000135914 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000026228 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: HTR2B 5-hydroxytryptamine (serotonin) receptor 2B".
  6. ^ Schmuck K, Ullmer C, Engels P, Lübbert H (Mar 1994). "Cloning and functional characterization of the human 5-HT2B serotonin receptor". FEBS Letters. 342 (1): 85–90. doi:10.1016/0014-5793(94)80590-3. PMID 8143856. S2CID 11232259.
  7. ^ Frazer A, Hensler HG (1999). "Serotonin". Basic Neurochemistry: Molecular, Cellular and Medical Aspects (6th ed.). Lippincott-Raven.
  8. ^ Bonhaus DW, Bach C, DeSouza A, Salazar FH, Matsuoka BD, Zuppan P, et al. (June 1995). "The pharmacology and distribution of human 5-hydroxytryptamine2B (5-HT2B) receptor gene products: comparison with 5-HT2A and 5-HT2C receptors". British Journal of Pharmacology. 115 (4): 622–8. doi:10.1111/j.1476-5381.1995.tb14977.x. PMC 1908489. PMID 7582481.
  9. ^ Enna SJ, Bylund DB, eds. (2008). XPharm : the comprehensive pharmacology reference. Amsterdam: Elsevier. ISBN 978-0-08-055232-3. OCLC 712018683.
  10. ^ a b Doly S, Valjent E, Setola V, Callebert J, Hervé D, Launay JM, et al. (Mar 2008). "Serotonin 5-HT2B receptors are required for 3,4-methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro". The Journal of Neuroscience. 28 (11): 2933–40. doi:10.1523/JNEUROSCI.5723-07.2008. PMC 6670669. PMID 18337424.
  11. ^ Launay JM, Hervé P, Peoc'h K, Tournois C, Callebert J, Nebigil CG, et al. (Oct 2002). "Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension" (PDF). Nature Medicine. 8 (10): 1129–35. doi:10.1038/nm764. PMID 12244304. S2CID 20736218.
  12. ^ Nebigil CG, Hickel P, Messaddeq N, Vonesch JL, Douchet MP, Monassier L, et al. (Jun 2001). "Ablation of serotonin 5-HT(2B) receptors in mice leads to abnormal cardiac structure and function". Circulation. 103 (24): 2973–9. doi:10.1161/01.cir.103.24.2973. PMID 11413089.
  13. ^ Elangbam CS, Job LE, Zadrozny LM, Barton JC, Yoon LW, Gates LD, et al. (Aug 2008). "5-hydroxytryptamine (5HT)-induced valvulopathy: compositional valvular alterations are associated with 5HT2B receptor and 5HT transporter transcript changes in Sprague-Dawley rats". Experimental and Toxicologic Pathology. 60 (4–5): 253–62. doi:10.1016/j.etp.2008.03.005. PMID 18511249.
  14. ^ Padhariya K, Bhandare R, Canney D, Velingkar V (2017-12-12). "Cardiovascular Concern of 5-HT2B Receptor and Recent Vistas in the Development of Its Antagonists". Cardiovascular & Hematological Disorders Drug Targets. 17 (2): 86–104. doi:10.2174/1871529X17666170703115111. PMID 28676029.
  15. ^ Neugebauer V (2020). "Serotonin—pain modulation". Handbook of the Behavioral Neurobiology of Serotonin. Vol. 31. Elsevier. pp. 309–320. doi:10.1016/b978-0-444-64125-0.00017-7. ISBN 9780444641250. S2CID 212837146.
  16. ^ Jaffré F, Callebert J, Sarre A, Etienne N, Nebigil CG, Launay JM, et al. (Aug 2004). "Involvement of the serotonin 5-HT2B receptor in cardiac hypertrophy linked to sympathetic stimulation: control of interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha cytokine production by ventricular fibroblasts". Circulation. 110 (8): 969–74. doi:10.1161/01.CIR.0000139856.20505.57. PMID 15302781.
  17. ^ Monassier L, Laplante MA, Jaffré F, Bousquet P, Maroteaux L, de Champlain J (Aug 2008). "Serotonin 5-HT(2B) receptor blockade prevents reactive oxygen species-induced cardiac hypertrophy in mice". Hypertension. 52 (2): 301–7. doi:10.1161/HYPERTENSIONAHA.107.105551. PMID 18591460.
  18. ^ Jaffré F, Bonnin P, Callebert J, Debbabi H, Setola V, Doly S, et al. (Jan 2009). "Serotonin and angiotensin receptors in cardiac fibroblasts coregulate adrenergic-dependent cardiac hypertrophy". Circulation Research. 104 (1): 113–23. doi:10.1161/CIRCRESAHA.108.180976. PMID 19023134.
  19. ^ Callebert J, Esteve JM, Hervé P, Peoc'h K, Tournois C, Drouet L, et al. (May 2006). "Evidence for a control of plasma serotonin levels by 5-hydroxytryptamine(2B) receptors in mice" (PDF). The Journal of Pharmacology and Experimental Therapeutics. 317 (2): 724–31. doi:10.1124/jpet.105.098269. PMID 16461587. S2CID 16099098.
  20. ^ Diaz SL, Maroteaux L (Sep 2011). "Implication of 5-HT(2B) receptors in the serotonin syndrome". Neuropharmacology. 61 (3): 495–502. doi:10.1016/j.neuropharm.2011.01.025. PMID 21277875. S2CID 14905808.
  21. ^ Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, et al. (Dec 2000). "Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications". Circulation. 102 (23): 2836–41. doi:10.1161/01.CIR.102.23.2836. PMID 11104741.
  22. ^ Fitzgerald LW, Burn TC, Brown BS, Patterson JP, Corjay MH, Valentine PA, et al. (Jan 2000). "Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine". Molecular Pharmacology. 57 (1): 75–81. PMID 10617681.
  23. ^ Roth BL (Jan 2007). "Drugs and valvular heart disease". The New England Journal of Medicine. 356 (1): 6–9. doi:10.1056/NEJMp068265. PMID 17202450.
  24. ^ "Archive: How Fen-Phen, a Diet 'Miracle,' Rose and Fell". archive.nytimes.com. Retrieved 2022-07-04.
  25. ^ Cavero I, Guillon JM (2014-03-01). "Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy". Journal of Pharmacological and Toxicological Methods. 69 (2): 150–161. doi:10.1016/j.vascn.2013.12.004. PMID 24361689.
  26. ^ PDB: 4IB4​; Wacker D, Wang C, Katritch V, Han GW, Huang XP, Vardy E, et al. (May 2013). "Structural features for functional selectivity at serotonin receptors". Science. 340 (6132): 615–9. Bibcode:2013Sci...340..615W. doi:10.1126/science.1232808. PMC 3644390. PMID 23519215.
  27. ^ Schuhmacher M (2007). [Chiral arylmethoxytryptamines as 5-HT2B-receptor antagonists: synthesis, analysis and in-vitro pharmacology] (German) (PDF) (Thesis). Ph.D. Dissertation. University of Regensburg. pp. 6–17. Archived from the original (PDF) on 2011-07-18. Retrieved 2008-08-11.
  28. ^ a b c Porter RH, Benwell KR, Lamb H, Malcolm CS, Allen NH, Revell DF, et al. (Sep 1999). "Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells". British Journal of Pharmacology. 128 (1): 13–20. doi:10.1038/sj.bjp.0702751. PMC 1571597. PMID 10498829.
  29. ^ Kennett GA, Trail B, Bright F (Dec 1998). "Anxiolytic-like actions of BW 723C86 in the rat Vogel conflict test are 5-HT2B receptor mediated". Neuropharmacology. 37 (12): 1603–10. doi:10.1016/S0028-3908(98)00115-4. PMID 9886683. S2CID 7310462.
  30. ^ McCorvy JD, Wacker D, Wang S, Agegnehu B, Liu J, Lansu K, et al. (August 2018). "Structural determinants of 5-HT2B receptor activation and biased agonism". Nature Structural & Molecular Biology. 25 (9): 787–796. doi:10.1038/s41594-018-0116-7. PMC 6237183. PMID 30127358.
  31. ^ Huang XP, Setola V, Yadav PN, Allen JA, Rogan SC, Hanson BJ, et al. (Oct 2009). "Parallel functional activity profiling reveals valvulopathogens are potent 5-hydroxytryptamine(2B) receptor agonists: implications for drug safety assessment". Molecular Pharmacology. 76 (4): 710–22. doi:10.1124/mol.109.058057. PMC 2769050. PMID 19570945.
  32. ^ a b Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, et al. (Jun 2003). "3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro". Molecular Pharmacology. 63 (6): 1223–1229. doi:10.1124/mol.63.6.1223. PMID 12761331. S2CID 839426.
  33. ^ Ray TS (2010). Manzoni OJ (ed.). "Psychedelics and the human receptorome". PLOS ONE. 5 (2): e9019. Bibcode:2010PLoSO...5.9019R. doi:10.1371/journal.pone.0009019. PMC 2814854. PMID 20126400.
  34. ^ Görnemann T, Hübner H, Gmeiner P, Horowski R, Latté KP, Flieger M, et al. (Mar 2008). "Characterization of the molecular fragment that is responsible for agonism of pergolide at serotonin 5-Hydroxytryptamine2B and 5-Hydroxytryptamine2A receptors". The Journal of Pharmacology and Experimental Therapeutics. 324 (3): 1136–45. doi:10.1124/jpet.107.133165. PMID 18096760. S2CID 24907300.
  35. ^ a b "PDSP Ki database, University of North Carolina at Chapel Hill". Retrieved 2019-09-04.
  36. ^ Millan MJ, Gobert A, Lejeune F, Dekeyne A, Newman-Tancredi A, Pasteau V, et al. (Sep 2003). "The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways". The Journal of Pharmacology and Experimental Therapeutics. 306 (3): 954–64. doi:10.1124/jpet.103.051797. PMID 12750432. S2CID 18753440.
  37. ^ Garnock-Jones KP (June 2017). "Cariprazine: A Review in Schizophrenia". CNS Drugs. 31 (6): 513–525. doi:10.1007/s40263-017-0442-z. PMID 28560619. S2CID 4392274.
  38. ^ Hofmann C, Penner U, Dorow R, Pertz HH, Jähnichen S, Horowski R, et al. (2006). "Lisuride, a dopamine receptor agonist with 5-HT2B receptor antagonist properties: absence of cardiac valvulopathy adverse drug reaction reports supports the concept of a crucial role for 5-HT2B receptor agonism in cardiac valvular fibrosis". Clinical Neuropharmacology. 29 (2): 80–6. doi:10.1097/00002826-200603000-00005. PMID 16614540. S2CID 33849447.
  39. ^ Egan CT, Herrick-Davis K, Miller K, Glennon RA, Teitler M (Apr 1998). "Agonist activity of LSD and lisuride at cloned 5HT2A and 5HT2C receptors". Psychopharmacology. 136 (4): 409–14. doi:10.1007/s002130050585. PMID 9600588. S2CID 3021798.
  40. ^ Beattie DT, Smith JA, Marquess D, Vickery RG, Armstrong SR, Pulido-Rios T, et al. (Nov 2004). "The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo". British Journal of Pharmacology. 143 (5): 549–60. doi:10.1038/sj.bjp.0705929. PMC 1575425. PMID 15466450.
  41. ^ Bonhaus DW, Flippin LA, Greenhouse RJ, Jaime S, Rocha C, Dawson M, et al. (Jul 1999). "RS-127445: a selective, high affinity, orally bioavailable 5-HT2B receptor antagonist". British Journal of Pharmacology. 127 (5): 1075–82. doi:10.1038/sj.bjp.0702632. PMC 1566110. PMID 10455251.
  42. ^ "Metadoxine extended release (MDX) for adult ADHD". Alcobra Ltd. 2014. Archived from the original on 2019-02-13. Retrieved 2014-05-07.
  43. ^ "promethazine | Activity data visualisation tool | IUPHAR/BPS Guide to PHARMACOLOGY". www.guidetopharmacology.org. Retrieved 2019-02-28.
  44. ^ Kovács A, Gacsályi I, Wellmann J, Schmidt E, Szücs Z, Dubreuil V, et al. (2003). "Effects of EGIS-7625, a selective and competitive 5-HT2B receptor antagonist". Cardiovascular Drugs and Therapy. 17 (5–6): 427–34. doi:10.1023/B:CARD.0000015857.96371.43. PMID 15107597. S2CID 11532969.
  45. ^ Dunlop J, Lock T, Jow B, Sitzia F, Grauer S, Jow F, et al. (Mar 2009). "Old and new pharmacology: positive allosteric modulation of the alpha7 nicotinic acetylcholine receptor by the 5-hydroxytryptamine(2B/C) receptor antagonist SB-206553 (3,5-dihydro-5-methyl-N-3-pyridinylbenzo[1,2-b:4,5-b']di pyrrole-1(2H)-carboxamide)". The Journal of Pharmacology and Experimental Therapeutics. 328 (3): 766–76. doi:10.1124/jpet.108.146514. PMID 19050173. S2CID 206500076.
  46. ^ Reavill C, Kettle A, Holland V, Riley G, Blackburn TP (Feb 1999). "Attenuation of haloperidol-induced catalepsy by a 5-HT2C receptor antagonist". British Journal of Pharmacology. 126 (3): 572–4. doi:10.1038/sj.bjp.0702350. PMC 1565856. PMID 10188965.
  47. ^ Poissonnet G, Parmentier JG, Boutin JA, Goldstein S (Mar 2004). "The emergence of selective 5-HT 2B antagonists structures, activities and potential therapeutic applications". Mini Reviews in Medicinal Chemistry. 4 (3): 325–30. doi:10.2174/1389557043487312. PMID 15032678.
  48. ^ Shyu KG (Jan 2009). "Serotonin 5-HT2B receptor in cardiac fibroblast contributes to cardiac hypertrophy: a new therapeutic target for heart failure?". Circulation Research. 104 (1): 1–3. doi:10.1161/CIRCRESAHA.108.191122. PMID 19118279. S2CID 41931843.
  49. ^ Moss N, Choi Y, Cogan D, Flegg A, Kahrs A, Loke P, et al. (Apr 2009). "A new class of 5-HT2B antagonists possesses favorable potency, selectivity, and rat pharmacokinetic properties". Bioorganic & Medicinal Chemistry Letters. 19 (8): 2206–10. doi:10.1016/j.bmcl.2009.02.126. PMID 19307114.
  50. ^ Ebrahimkhani MR, Oakley F, Murphy LB, Mann J, Moles A, Perugorria MJ, et al. (Dec 2011). "Stimulating healthy tissue regeneration by targeting the 5-HT2B receptor in chronic liver disease". Nature Medicine. 17 (12): 1668–73. doi:10.1038/nm.2490. PMC 3428919. PMID 22120177.

Further reading[edit]

External links[edit]

  • "5-HT2B". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2017-02-02. Retrieved 2008-11-25.
  • Human HTR2B genome location and HTR2B gene details page in the UCSC Genome Browser.
  • Overview of all the structural information available in the PDB for UniProt: P41595 (5-hydroxytryptamine receptor 2B) at the PDBe-KB.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

Retrieved from "https://en.wikipedia.org/w/index.php?title=5-HT2B_receptor&oldid=1233647306"