5-HT2B receptor

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5-hydroxytryptamine (serotonin) receptor 2B, G protein-coupled
4IB4.png
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols HTR2B ; 5-HT(2B); 5-HT2B
External IDs OMIM601122 MGI109323 HomoloGene55492 IUPHAR: 7 ChEMBL: 1833 GeneCards: HTR2B Gene
RNA expression pattern
PBB GE HTR2B 206638 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 3357 15559
Ensembl ENSG00000135914 ENSMUSG00000026228
UniProt P41595 Q02152
RefSeq (mRNA) NM_000867 NM_008311
RefSeq (protein) NP_000858 NP_032337
Location (UCSC) Chr 2:
231.97 – 231.99 Mb
Chr 1:
86.1 – 86.11 Mb
PubMed search [1] [2]

5-Hydroxytryptamine receptor 2B (5-HT2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2B gene.[1][2] 5-HT2B is a member of the 5-HT2 receptor family that binds the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT).

Function[edit]

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 effects include neuronal sensitization to tactile stimuli and mediation of some of the effects of hallucinogenic substituted amphetamines.

The 5-HT2B receptor subtype is involved in:

  • CNS: presynaptic inhibition, behavioural effects[3]
  • Vascular: pulmonary vasoconstriction[4]
  • Cardiac: The 5-HT2B receptor regulates cardiac structure and functions as demonstrated by the abnormal cardiac development observed in 5-HT2B receptor null mice.[5] The 5-HT2B receptor stimulation can also lead to pathological proliferation of cardiac valves fibroblasts,[6] which with chronic overstimulation of 5-HT2B can lead to a severe valvulopathy. Moreover, 5-HT2B receptors were recently shown to be overexpressed in human failing heart and antagonists of 5-HT2B receptors were uncovered to prevent both angiotensin II or beta-adrenergic agonist-induced pathological cardiac hypertrophy in mouse.[7][8][9]
  • 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,[10] and with the abnormal acute serotonin release produced by drugs such as MDMA.[3] Surprisingly however 5-HT2B receptor activation appears to be protective against the development of serotonin syndrome following elevated extracellular serotonin levels,[11] despite its role in modulating serotonin release.

Clinical significance[edit]

5-HT2B receptors have also been strongly implicated in drug-induced valvular heart disease.[12][13][14] In this context, it is generally considered to be an antitarget.

The structure of the 5-HT2B receptor was recently solved in complex with the valvulopathogenic drug ergotamine.[15]

Ligands[edit]

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.[16]

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.[32] More recent research has focused on possible application of 5-HT2B antagonists as treatments for chronic heart disease.[33][34] Research claims serotonin 5-HT2B receptors have effect on liver regeneration.[35]

See also[edit]

References[edit]

  1. ^ "Entrez Gene: HTR2B 5-hydroxytryptamine (serotonin) receptor 2B". 
  2. ^ 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. 
  3. ^ 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. PMID 18337424. 
  4. ^ 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". Nature Medicine 8 (10): 1129–35. doi:10.1038/nm764. PMID 12244304. 
  5. ^ 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. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ 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. 
  10. ^ 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". The Journal of Pharmacology and Experimental Therapeutics 317 (2): 724–31. doi:10.1124/jpet.105.098269. PMID 16461587. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ 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. 
  14. ^ 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. 
  15. ^ 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. doi:10.1126/science.1232808. PMID 23519215. 
  16. ^ Schuhmacher M (2007). "[Chiral arylmethoxytryptamines as 5-HT2B-receptor antagonists: synthesis, analysis and in-vitro pharmacology] (German)" (PDF). Ph.D. Dissertation. University of Regensburg. pp. pages 6–17. Retrieved 2008-08-11. 
  17. ^ 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. 
  18. ^ 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. 
  19. ^ a b PDSP Ki database, University of North Carolina at Chapel Hill. http://pdsp.med.unc.edu/pdsp.php
  20. ^ 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). doi:10.1124/mol.109.058057. PMID 19570945. 
  21. ^ 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. 
  22. ^ Ray TS (2010). Manzoni OJ, ed. "Psychedelics and the human receptorome". PloS One 5 (2): e9019. doi:10.1371/journal.pone.0009019. PMC 2814854. PMID 20126400. 
  23. ^ 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. 
  24. ^ 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. 
  25. ^ 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. 
  26. ^ 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. 
  27. ^ 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. 
  28. ^ 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. 
  29. ^ 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 / Sponsored by the International Society of Cardiovascular Pharmacotherapy 17 (5-6): 427–34. doi:10.1023/B:CARD.0000015857.96371.43. PMID 15107597. 
  30. ^ 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. 
  31. ^ 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. 
  32. ^ 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. 
  33. ^ 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. 
  34. ^ 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. 
  35. ^ 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. 

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