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5-hydroxytryptamine (serotonin) receptor 2B
Identifiers
Symbols HTR2B; 5-HT(2B); 5-HT2B
External IDs OMIM601122 MGI109323 HomoloGene55492 IUPHAR: 5-HT2B 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 Q7TNN4
RefSeq (mRNA) NM_000867 NM_008311
RefSeq (protein) NP_000858 NP_032337
Location (UCSC) Chr 2:
231.68 - 231.7 Mb
Chr 1:
87.93 - 87.94 Mb
PubMed search [1] [2]

5-hydroxytryptamine (serotonin) receptor 2B, also known as HTR2B, is a 5-HT2 receptor, but also denotes the human gene encoding it.[1][2]

Contents

Function

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 phenylisopropylamine hallucinogens.

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]

Ligands

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 5HT2B agonists, and the lack of clear therapeutic application for 5HT2B antagonists, but there is still a need for selective ligands for scientific research.[11]

Agonists

Selective
  • BW-723C86:[12] fair functional subtype selectivity; almost full agonist. Anxiolytic in vivo.[13]
  • Ro60-0175 [12] functionally selective over 5-HT2A, potent agonist at both 5-HT2B and 5-HT2C
  • α-Methyl-5-HT - moderately selective over 5-HT2A and 5-HT2C
Non-selective

Antagonists

Possible Applications

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.[22] More recent research has focused on possible application of 5-HT2B antagonists as treatments for chronic heart disease.[23][24]

See also

References

  1. ^ "Entrez Gene: HTR2B 5-hydroxytryptamine (serotonin) receptor 2B". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3357.  
  2. ^ Schmuck K, Ullmer C, Engels P, Lübbert H (March 1994). "Cloning and functional characterization of the human 5-HT2B serotonin receptor". FEBS Lett. 342 (1): 85–90. doi:10.1016/0014-5793(94)80590-3. PMID 8143856. http://linkinghub.elsevier.com/retrieve/pii/0014-5793(94)80590-3.  
  3. ^ a b Doly S, Valjent E, Setola V, Callebert J, Hervé D, Launay JM, Maroteaux L (March 2008). "Serotonin 5-HT2B receptors are required for 3,4-methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro". J. Neurosci. 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, Etienne N, Drouet L, Humbert M, Simonneau G, Maroteaux L (October 2002). "Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension". Nat. Med. 8 (10): 1129–35. doi:10.1038/nm764. PMID 12244304.  
  5. ^ Nebigil CG, Hickel P, Messaddeq N, Vonesch JL, Douchet MP, Monassier L, György K, Matz R, Andriantsitohaina R, Manivet P, Launay JM, Maroteaux L (June 2001). "Ablation of serotonin 5-HT(2B) receptors in mice leads to abnormal cardiac structure and function". Circulation 103 (24): 2973–9. PMID 11413089. http://circ.ahajournals.org/cgi/content/abstract/103/24/2973.  
  6. ^ Elangbam CS, Job LE, Zadrozny LM, Barton JC, Yoon LW, Gates LD, Slocum N (August 2008). "5-hydroxytryptamine (5HT)-induced valvulopathy: compositional valvular alterations are associated with 5HT2B receptor and 5HT transporter transcript changes in Sprague-Dawley rats". Exp. Toxicol. Pathol. 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, Maroteaux L, Monassier L (August 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 (August 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, Monassier L, Mettauer B, Blaxall BC, Launay JM, Maroteaux L (November 2008). "Serotonin and Angiotensin Receptors in Cardiac Fibroblasts Coregulate Adrenergic-Dependent Cardiac Hypertrophy". Circ. Res. 104: 113. doi:10.1161/CIRCRESAHA.108.180976. PMID 19023134.  
  10. ^ Callebert J, Esteve JM, Hervé P, Peoc'h K, Tournois C, Drouet L, Launay JM, Maroteaux L (May 2006). "Evidence for a control of plasma serotonin levels by 5-hydroxytryptamine(2B) receptors in mice". J. Pharmacol. Exp. Ther. 317 (2): 724–31. doi:10.1124/jpet.105.098269. PMID 16461587.  
  11. ^ Schuhmacher M (2007). [Chiral arylmethoxytryptamines as 5-HT2B-receptor antagonists: synthesis, analysis and in-vitro pharmacology (German)]. Ph.D. Dissertation. University of Regensburg. pp. pages 6-17. http://www.opus-bayern.de/uni-regensburg/volltexte/2008/796/pdf/Dissertation_Schumacher.pdf. Retrieved 2008-08-11.  
  12. ^ a b c Porter RH, Benwell KR, Lamb H, et al. (1999). "Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells". Br. J. Pharmacol. 128 (1): 13–20. doi:10.1038/sj.bjp.0702751. PMID 10498829.  
  13. ^ Kennett GA, Trail B, Bright F (December 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.  
  14. ^ a b Setola, Vincent; Sandra J Hufeisen, K Jane Grande-Allen, Ivan Vesely, Richard A Glennon, Bruce Blough, Richard B Rothman, Bryan L Roth (Jan 7 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.  
  15. ^ Görnemann T, Hübner H, Gmeiner P, et al. (2008). "Characterization of the molecular fragment that is responsible for agonism of pergolide at serotonin 5-Hydroxytryptamine2B and 5-Hydroxytryptamine2A receptors". J. Pharmacol. Exp. Ther. 324 (3): 1136–45. doi:10.1124/jpet.107.133165. PMID 18096760.  
  16. ^ Hofmann C, Penner U, Dorow R, Pertz HH, Jähnichen S, Horowski R, Latté KP, Palla D, Schurad B (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". Clin Neuropharmacol 29 (2): 80–6. doi:10.1097/00002826-200603000-00005. PMID 16614540. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?an=00002826-200603000-00005.  
  17. ^ Beattie DT, Smith JA, Marquess D, et al. (November 2004). "The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo". Br. J. Pharmacol. 143 (5): 549–60. doi:10.1038/sj.bjp.0705929. PMID 15466450.  
  18. ^ Bonhaus DW, Flippin LA, Greenhouse RJ, et al. (1999). "RS-127445: a selective, high affinity, orally bioavailable 5-HT2B receptor antagonist". Br. J. Pharmacol. 127 (5): 1075–82. doi:10.1038/sj.bjp.0702632. PMID 10455251.  
  19. ^ Kovács A, Gacsályi I, Wellmann J, et al. (2003). "Effects of EGIS-7625, a selective and competitive 5-HT2B receptor antagonist". Cardiovasc Drugs Ther 17 (5-6): 427–34. PMID 15107597.  
  20. ^ Dunlop J, Lock T, Jow B, et al. (March 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)". J. Pharmacol. Exp. Ther. 328 (3): 766–76. doi:10.1124/jpet.108.146514. PMID 19050173.  
  21. ^ Reavill C, Kettle A, Holland V, Riley G, Blackburn TP (February 1999). "Attenuation of haloperidol-induced catalepsy by a 5-HT2C receptor antagonist". Br. J. Pharmacol. 126 (3): 572–4. doi:10.1038/sj.bjp.0702350. PMID 10188965.  
  22. ^ Poissonnet G, Parmentier JG, Boutin JA, Goldstein S (March 2004). "The emergence of selective 5-HT 2B antagonists structures, activities and potential therapeutic applications". Mini Rev Med Chem 4 (3): 325–30. doi:10.2174/1389557043487312. PMID 15032678.  
  23. ^ Shyu KG (January 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.  
  24. ^ Moss N, Choi Y, Cogan D, Flegg A, Kahrs A, Loke P, Meyn O, Nagaraja R, Napier S, Parker A, Thomas Peterson J, Ramsden P, Sarko C, Skow D, Tomlinson J, Tye H, Whitaker M (April 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.  

External links

Further reading

  • Raymond JR, Mukhin YV, Gelasco A, et al. (2002). "Multiplicity of mechanisms of serotonin receptor signal transduction.". Pharmacol. Ther. 92 (2-3): 179–212. doi:10.1016/S0163-7258(01)00169-3. PMID 11916537.  
  • Bonhaus DW, Bach C, DeSouza A, et al. (1995). "The pharmacology and distribution of human 5-hydroxytryptamine2B (5-HT2B) receptor gene products: comparison with 5-HT2A and 5-HT2C receptors.". Br. J. Pharmacol. 115 (4): 622–8. PMID 7582481.  
  • Choi DS, Birraux G, Launay JM, Maroteaux L (1994). "The human serotonin 5-HT2B receptor: pharmacological link between 5-HT2 and 5-HT1D receptors.". FEBS Lett. 352 (3): 393–9. doi:10.1016/0014-5793(94)00968-6. PMID 7926008.  
  • Kursar JD, Nelson DL, Wainscott DB, Baez M (1994). "Molecular cloning, functional expression, and mRNA tissue distribution of the human 5-hydroxytryptamine2B receptor.". Mol. Pharmacol. 46 (2): 227–34. PMID 8078486.  
  • Schmuck K, Ullmer C, Engels P, Lübbert H (1994). "Cloning and functional characterization of the human 5-HT2B serotonin receptor.". FEBS Lett. 342 (1): 85–90. doi:10.1016/0014-5793(94)80590-3. PMID 8143856.  
  • Launay JM, Birraux G, Bondoux D, et al. (1996). "Ras involvement in signal transduction by the serotonin 5-HT2B receptor.". J. Biol. Chem. 271 (6): 3141–7. doi:10.1074/jbc.271.6.3141. PMID 8621713.  
  • Le Coniat M, Choi DS, Maroteaux L, et al. (1996). "The 5-HT2B receptor gene maps to 2q36.3-2q37.1.". Genomics 32 (1): 172–3. doi:10.1006/geno.1996.0101. PMID 8786115.  
  • Kim SJ, Veenstra-VanderWeele J, Hanna GL, et al. (2000). "Mutation screening of human 5-HT(2B)receptor gene in early-onset obsessive-compulsive disorder.". Mol. Cell. Probes 14 (1): 47–52. doi:10.1006/mcpr.1999.0281. PMID 10722792.  
  • Manivet P, Mouillet-Richard S, Callebert J, et al. (2000). "PDZ-dependent activation of nitric-oxide synthases by the serotonin 2B receptor.". J. Biol. Chem. 275 (13): 9324–31. doi:10.1074/jbc.275.13.9324. PMID 10734074.  
  • Becamel C, Figge A, Poliak S, et al. (2001). "Interaction of serotonin 5-hydroxytryptamine type 2C receptors with PDZ10 of the multi-PDZ domain protein MUPP1.". J. Biol. Chem. 276 (16): 12974–82. doi:10.1074/jbc.M008089200. PMID 11150294.  
  • Manivet P, Schneider B, Smith JC, et al. (2002). "The serotonin binding site of human and murine 5-HT2B receptors: molecular modeling and site-directed mutagenesis.". J. Biol. Chem. 277 (19): 17170–8. doi:10.1074/jbc.M200195200. PMID 11859080.  
  • Borman RA, Tilford NS, Harmer DW, et al. (2002). "5-HT(2B) receptors play a key role in mediating the excitatory effects of 5-HT in human colon in vitro.". Br. J. Pharmacol. 135 (5): 1144–51. doi:10.1038/sj.bjp.0704571. PMID 11877320.  
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  • Matsuda A, Suzuki Y, Honda G, et al. (2003). "Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways.". Oncogene 22 (21): 3307–18. doi:10.1038/sj.onc.1206406. PMID 12761501.  
  • Slominski A, Pisarchik A, Zbytek B, et al. (2003). "Functional activity of serotoninergic and melatoninergic systems expressed in the skin.". J. Cell. Physiol. 196 (1): 144–53. doi:10.1002/jcp.10287. PMID 12767050.  
  • Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMID 15489334.  
  • Lin Z, Walther D, Yu XY, et al. (2005). "The human serotonin receptor 2B: coding region polymorphisms and association with vulnerability to illegal drug abuse.". Pharmacogenetics 14 (12): 805–11. doi:10.1097/00008571-200412000-00003. PMID 15608559.  
  • Hillier LW, Graves TA, Fulton RS, et al. (2005). "Generation and annotation of the DNA sequences of human chromosomes 2 and 4.". Nature 434 (7034): 724–31. doi:10.1038/nature03466. PMID 15815621.  

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








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