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
editFirst 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
edit5-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
editThe 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
- BW-723C86[28] – fair functional subtype selectivity; almost full agonist. Anxiolytic in vivo[29]
- Ro60-0175[28] – functionally selective over 5-HT2A, potent agonist at both 5-HT2B/C
- VER-3323 – selective for 5-HT2B/C over 5-HT2A
- α-Methyl-5-HT – moderately selective over 5-HT2A/C
- 6-APB
- LY-266,097 – biased partial agonist in favor of Gq protein, no β-arrestin2 recruitment[30]
- VU6067416
- Non-selective
- Guanfacine – an α2A agonist, but has 5-HT2B agonistic activity at therapeutic concentrations.[31]
- MDMA[32]
- MDA[32]
- MEM[33]
- Pergolide[34]
- Cabergoline
- Norfenfluramine[28]
- Aminorex
- Bromo-dragonfly
- DMT
- 5-MeO-DMT
- LSD – about equal affinity for human cloned 5-HT2B and 5-HT2A receptors[35]
- Psilocin[35]
- Xylometazoline
- Oxymetazoline
- Quinidine
- Ropinirole
- Fenoldopam
- Lorcaserin
- Methylergonovine
- Ergotamine
- Ergonovine
Antagonists
edit- Agomelatine – primarily a melatonin MT1/MT2 receptor agonist, with a less potent antagonism of 5-HT2B and 5-HT2C[36]
- Amisulpride
- Aripiprazole
- Cariprazine[37]
- Clozapine
- Cyproheptadine
- mCPP (in humans)
- Sarpogrelate – a mixed 5-HT2A/B antagonist
- Lisuride – a dopamine agonist of the ergoline class, that is also a 5-HT2B antagonist[38] and a dual 5-HT2A/C agonist[39]
- Tegaserod – primarily a 5-HT4 agonist, but also a 5-HT2B antagonist[40]
- RS-127,445[41] – high affinity; subtype selective (1000×), selective over at least eight other 5-HTR types; orally bioavailable
- Metadoxine – a 5-HT2B antagonist and GABA-activity modulator[42]
- SDZ SER-082 – a mixed 5-HT2B/C antagonist
- Promethazine[43]
- EGIS-7625 – high selectivity over 5-HT2A[44]
- PRX-08066
- SB-200,646
- SB-204,741
- SB-206,553 – mixed 5-HT2B/C antagonist and PAM at α7 nAChR[45]
- SB-215,505[46]
- SB-228,357
- Terguride – an oral, potent antagonist of 5-HT2A and 5-HT2B receptors
- LY-266,097
- LY-272,015
Peripherally selective antagonists
editPossible applications
edit5-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.[48] More recent research has focused on possible application of 5-HT2B antagonists as treatments for chronic heart disease.[49][50] Research claims serotonin 5-HT2B receptors have effect on liver regeneration.[51] Antagonism of 5-HT2B may attenuate fibrogenesis and improve liver function in disease models in which fibrosis is pre-established and progressive.
See also
editReferences
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Further reading
edit- Raymond JR, Mukhin YV, Gelasco A, Turner J, Collinsworth G, Gettys TW, et al. (2002). "Multiplicity of mechanisms of serotonin receptor signal transduction". Pharmacology & Therapeutics. 92 (2–3): 179–212. doi:10.1016/S0163-7258(01)00169-3. PMID 11916537.
- Choi DS, Birraux G, Launay JM, Maroteaux L (Oct 1994). "The human serotonin 5-HT2B receptor: pharmacological link between 5-HT2 and 5-HT1D receptors". FEBS Letters. 352 (3): 393–9. doi:10.1016/0014-5793(94)00968-6. PMID 7926008. S2CID 26931598.
- Kursar JD, Nelson DL, Wainscott DB, Baez M (Aug 1994). "Molecular cloning, functional expression, and mRNA tissue distribution of the human 5-hydroxytryptamine2B receptor". Molecular Pharmacology. 46 (2): 227–34. PMID 8078486.
- 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.
- Launay JM, Birraux G, Bondoux D, Callebert J, Choi DS, Loric S, et al. (Feb 1996). "Ras involvement in signal transduction by the serotonin 5-HT2B receptor". The Journal of Biological Chemistry. 271 (6): 3141–7. doi:10.1074/jbc.271.6.3141. PMID 8621713.
- Le Coniat M, Choi DS, Maroteaux L, Launay JM, Berger R (Feb 1996). "The 5-HT2B receptor gene maps to 2q36.3-2q37.1" (PDF). Genomics. 32 (1): 172–3. doi:10.1006/geno.1996.0101. PMID 8786115.
- Kim SJ, Veenstra-VanderWeele J, Hanna GL, Gonen D, Leventhal BL, Cook EH (Feb 2000). "Mutation screening of human 5-HT(2B)receptor gene in early-onset obsessive-compulsive disorder". Molecular and Cellular Probes. 14 (1): 47–52. doi:10.1006/mcpr.1999.0281. PMID 10722792.
- Manivet P, Mouillet-Richard S, Callebert J, Nebigil CG, Maroteaux L, Hosoda S, et al. (Mar 2000). "PDZ-dependent activation of nitric-oxide synthases by the serotonin 2B receptor". The Journal of Biological Chemistry. 275 (13): 9324–31. doi:10.1074/jbc.275.13.9324. PMID 10734074.
- Becamel C, Figge A, Poliak S, Dumuis A, Peles E, Bockaert J, et al. (Apr 2001). "Interaction of serotonin 5-hydroxytryptamine type 2C receptors with PDZ10 of the multi-PDZ domain protein MUPP1". The Journal of Biological Chemistry. 276 (16): 12974–82. doi:10.1074/jbc.M008089200. PMID 11150294.
- Manivet P, Schneider B, Smith JC, Choi DS, Maroteaux L, Kellermann O, et al. (May 2002). "The serotonin binding site of human and murine 5-HT2B receptors: molecular modeling and site-directed mutagenesis". The Journal of Biological Chemistry. 277 (19): 17170–8. doi:10.1074/jbc.M200195200. PMID 11859080.
- Borman RA, Tilford NS, Harmer DW, Day N, Ellis ES, Sheldrick RL, et al. (Mar 2002). "5-HT(2B) receptors play a key role in mediating the excitatory effects of 5-HT in human colon in vitro". British Journal of Pharmacology. 135 (5): 1144–51. doi:10.1038/sj.bjp.0704571. PMC 1573235. PMID 11877320.
- Matsuda A, Suzuki Y, Honda G, Muramatsu S, Matsuzaki O, Nagano Y, et al. (May 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. S2CID 38880905.
- Slominski A, Pisarchik A, Zbytek B, Tobin DJ, Kauser S, Wortsman J (Jul 2003). "Functional activity of serotoninergic and melatoninergic systems expressed in the skin". Journal of Cellular Physiology. 196 (1): 144–53. doi:10.1002/jcp.10287. PMID 12767050. S2CID 24534729.
- Lin Z, Walther D, Yu XY, Drgon T, Uhl GR (Dec 2004). "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.
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.