5-HT2B receptor

HTR2B
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4NC3, 4IB4
Identifiers
Aliases	HTR2B , 5-HT(2B), 5-HT2B, 5-HT-2B, 5-hydroxytryptamine receptor 2B
External IDs	OMIM: 601122; MGI: 109323; HomoloGene: 55492; GeneCards: HTR2B; OMA:HTR2B - orthologs
Gene location (Human) Chr. Chromosome 2 (human) [1] Band 2q37.1 Start 231,108,230 bp [1] End 231,125,042 bp [1]
Gene location (Mouse) Chr. Chromosome 1 (mouse) [2] Band 1|1 C5 Start 86,026,748 bp [2] End 86,039,692 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in decidua tail of epididymis stromal cell of endometrium caput epididymis corpus epididymis left adrenal gland left adrenal cortex right adrenal cortex smooth muscle tissue testicle Top expressed in decidua morula neural groove neural fold embryo tail of embryo genital tubercle calvaria right lung lobe right kidney More reference expression data BioGPS More reference expression data
Gene ontology Molecular function G protein-coupled receptor activity GTPase activator activity signal transducer activity G protein-coupled serotonin receptor activity G-protein alpha-subunit binding serotonin binding neurotransmitter receptor activity Cellular component cytoplasm integral component of membrane membrane plasma membrane synapse cell junction neuron projection integral component of plasma membrane nucleoplasm dendrite Biological process intestine smooth muscle contraction smooth muscle contraction G protein-coupled receptor internalization release of sequestered calcium ion into cytosol regulation of behavior positive regulation of endothelial cell proliferation positive regulation of MAP kinase activity phosphorylation positive regulation of cytokine production vasoconstriction ERK1 and ERK2 cascade positive regulation of phosphatidylinositol biosynthetic process cardiac muscle hypertrophy heart morphogenesis cellular calcium ion homeostasis neural crest cell differentiation negative regulation of apoptotic process negative regulation of cell death activation of phospholipase C activity protein kinase C signaling cGMP biosynthetic process cellular response to temperature stimulus positive regulation of GTPase activity heart development positive regulation of nitric-oxide synthase activity protein kinase C-activating G protein-coupled receptor signaling pathway embryonic morphogenesis serotonin receptor signaling pathway neural crest cell migration positive regulation of cell population proliferation positive regulation of ERK1 and ERK2 cascade positive regulation of I-kappaB kinase/NF-kappaB signaling phosphatidylinositol 3-kinase signaling negative regulation of autophagy positive regulation of cell division calcium-mediated signaling signal transduction phospholipase C-activating G protein-coupled receptor signaling pathway G protein-coupled serotonin receptor signaling pathway G protein-coupled receptor signaling pathway animal behavior cGMP-mediated signaling G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger chemical synaptic transmission Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 1: 86.03 – 86.04 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

5-Hydroxytryptamine receptor 2B (5-HT_2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2B gene. ^{[5] [6]} 5-HT_2B 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-HT_2B receptor is G_q/G₁₁-protein coupled, leading to downstream activation of phospholipase C.

Tissue distribution and function

First discovered in the stomach of rats, 5-HT_2B was challenging to characterize initially because of its structural similarity to the other 5-HT₂ receptors, particularly 5-HT_2C. ^[7] The 5-HT₂ receptors (of which the 5-HT_2B 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-HT_2B 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-HT_2B receptor subtype is involved in:

• CNS: inhibition of serotonin and dopamine uptake, behavioral effects ^[10]
• Vascular: pulmonary vasoconstriction ^[11]
• Cardiac: The 5-HT_2B receptor regulates cardiac structure and functions, as demonstrated by the abnormal cardiac development observed in 5-HT_2B 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-HT_2B receptors were discovered to prevent both angiotensin II or beta-adrenergic agonist-induced pathological cardiac hypertrophy in mouse. ^{[16] [17] [18]}
• Serotonin transporter: 5-HT_2B 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-HT_2B 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

5-HT_2B 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-HT_2B stimulation. ^[24] Today, 5-HT_2B agonism is considered a toxicity signal precluding further clinical development of a compound. ^[25]

Ligands

The structure of the 5-HT_2B receptor was resolved in a complex with the valvulopathogenic drug ergotamine. ^[26] As of 2009, few highly selective 5-HT_2B receptor ligands have been discovered, although numerous potent non-selective compounds are known, particularly agents with concomitant 5-HT_2C binding. Research in this area has been limited due to the cardiotoxicity of 5-HT_2B agonists, and the lack of clear therapeutic application for 5-HT_2B antagonists, but there is still a need for selective ligands for scientific research. ^[27]

Agonists

Endogenous

• 5-Methoxytryptamine (5-MT) – trace amine ^{[28] [29]}
• DMT – trace amine ^{[30] [31] [32] [33]}
• Serotonin – neurotransmitter, K_D ≈ 10 nM ^{[34] [35] [36]}
• Tryptamine – trace amine ^{[34] [36]}

Selective

• 6-APB – ~100-fold selectivity over the 5-HT_2A and 5-HT_2C receptors, ≥32-fold selectivity over monoamine release, ~12-fold selectivity over α_2C-adrenergic receptor ^{[30] [37]}
• α-Methylserotonin – ~10-fold selectivity over 5-HT_2A and 5-HT_2C ^{[34] [38] [36]}
• BW-723C86 – 100-fold selectivity over 5-HT_2A but only 3- to 10-fold selectivity over 5-HT_2C, ^{[34] [39]} fair functional subtype selectivity, almost full agonist, anxiolytic in vivo ^[40]
• LY-266,097 – biased partial agonist in favor of G_q protein, no β-arrestin2 recruitment ^[41]
• VU6067416 – modest selectivity over 5-HT_2A and 5-HT_2C ^[42]

Non-selective

• 25C-NBOMe ^{[30] [43]}
• 25I-NBOMe ^{[30] [43]}
• 2C-B ^{[30] [43]}
• 2C-B-FLY ^{[30] [44]}
• 2C-C ^{[30] [43]}
• 2C-D ^{[30] [43]}
• 2C-E ^{[30] [43]}
• 2C-I ^{[30] [43]}
• 4-Methylamphetamine ^[30]
• 5-APB ^{[30] [45] [37]}
• 5-APDB ^[30]
• 5-Carboxamidotryptamine ^[36]
• 5-MAPB ^[45]
• 6-APB ^[37]
• 6-APDB ^[30]
• 6-MAPB ^[45]
• 5-MeO-αMT ^{[30] [32]}
• 5-MeO-DiPT
• 5-MeO-DMT ^[42]
• 5-MeO-MiPT ^{[30] [32]}
• AL-38022A ^[46]
• Aminorex (weakly) ^{[47] [48]}
• Ariadne ^[49]
• Benfluorex ^[50]
• Bromo-dragonfly ^{[44] [51] [52]}
• Bromocriptine ^[53]
• Cabergoline ^{[54] [35]}
• Chlorphentermine (very weakly) ^[47]
• CYB210010 (2C-T-TFM) ^{[55] [56]}
• Dexfenfluramine ^[57]
• Dexnorfenfluramine ^[57]
• Dihydroergocryptine ^[58]
• Dihydroergotamine ^{[54] [59]}
• DiPT ^{[30] [32]}
• DOB ^{[30] [36]}
• DOC ^[30]
• DOET ^[60]
• DOI ^{[30] [36] [35]}
• DOM ^{[30] [60]}
• Ergometrine (ergonovine) ^[54]
• Ergotamine ^{[54] [57] [35]}
• Fenfluramine ^{[57] [35]}
• Fenoldopam ^[35]
• Guanfacine – an α_2A-adrenergic agonist, but has 5-HT_2B agonistic activity at therapeutic concentrations ^{[35] [61]}
• Levofenfluramine ^[57]
• Levonorfenfluramine ^[57]
• Lorcaserin ^[54]
• LSD – about equal affinity for human cloned 5-HT_2B and 5-HT_2A receptors ^{[62] [32] [63]}
• LSM-775 ^[64]
• mCPP (in humans; weak partial agonist) ^{[57] [36]}
• MDA ^{[30] [65]}
• MDMA ^{[33] [65]}
• MEM ^[66]
• Mescaline ^[33]
• Methylergometrine (methylergonovine) ^{[54] [57] [35]}
• Methysergide (antagonist in some studies) ^{[57] [35] [67]}
• Naphthylaminopropane ^[68]
• Norfenfluramine ^{[57] [35] [39]}
• ORG-12962 ^[36]
• ORG-37684 ^[67]
• Oxymetazoline ^[35]
• Pergolide ^{[54] [35] [69]}
• PNU-22394
• Psilocin ^{[62] [63]}
• Psilocybin ^[63]
• Quipazine (weak partial agonist) ^[36]
• Ro60-0175 – functionally selective over 5-HT_2A, potent agonist at both 5-HT_2B/C ^{[34] [39]}
• Ropinirole ^[35]
• Quinidine ^[35]
• TFMPP (weak partial agonist) ^[36]
• VER-3323 – mixed 5-HT_2C and 5-HT_2B agonist with weaker 5-HT_2A affinity ^[67]
• Xylometazoline ^[35]

Peripherally selective

• AL-34662 – non-selective over 5-HT_2A and 5-HT_2C ^[70]

Inactive

A number of notable drugs appear to be inactive or very weak as serotonin 5-HT_2B receptor agonists, at least in vitro . ^[30] These include the stimulants and/or entactogens dextroamphetamine, dextromethamphetamine, 4-fluoroamphetamine, 4-fluoromethamphetamine, phentermine, methylone, mephedrone, MDAI, and MMAI, among others. ^{[30] [47] [37] [71] [72] [73]} Findings are somewhat conflicting for certain psychedelics, such as psilocin and LSD, but most studies find that these drugs are indeed potent serotonin 5-HT_2B receptor agonists. ^{[63] [30] [32]}

Antagonists

Selective

• 5-HCPC ^{[74] [75]}
• 5-HPEC (weak) ^[74]
• 5-HPPC ^[74]
• AM1125 ^[74]
• AM1476 ^[74]
• BF-1 – derived from pimethixene ^{[74] [76] [77]}
• EGIS-7625 – high selectivity over 5-HT_2A ^{[76] [78] [79]}
• EXT5 – highly selective ^{[74] [80]}
• EXT9 – somewhat selective ^{[74] [80]}
• LY-23,728 ^[81]
• LY-266,097 – pK_i = 9.7, 100-fold selectivity over 5-HT_2A and 5-HT_2C ^{[34] [81]}
• LY-272,015 – fairly selective and highly potent ^[34]
• LY-287,375 ^{[81] [82]}
• MRS7925 – substantially selective over 5-HT_2A and 5-HT_2C but minimal selectivity over the adenosine A₁ receptor ^[83]
• MRS8209 ^[84]
• MW071 (MW01-8-071HAB) – non-MAOI minaprine analogue ^[85]
• PRX-08066 – K_i ≈ 1.7 nM, >100-fold selectivity ^{[74] [76] [34]}
• RQ-00310941 (RQ-941) – K_i = 2.0 nM, IC₅₀ = 17 nM, >2,000-fold selectivity against >60 targets, under development for medical use ^{[74] [86] [87]}
• RS-127,445 (MT-500) – K_i = 0.3 nM, >1,000-fold selectivity over 5-HT_2A and 5-HT_2C and numerous other targets, selective over at least eight other serotonin receptors, developed for clinical use but discontinued ^{[74] [34] [76] [88] [67]}
• SB-204,741 – >135-fold selectivity over 5-HT_2C and 5-HT_2A ^[89]
• SB-215,505 – mixed 5-HT_2B and 5-HT_2C antagonist ^{[34] [76] [90]}
• VU6047534 – weak partial agonist or antagonist, peripherally selective in mice but not humans ^{[91] [92]}

Non-selective

• 2-Bromo-LSD (BOL-148; bromolysergide) ^[93]
• (–)-MBP – 5-HT_2A antagonist, 5-HT_2B inverse agonist, and 5-HT_2C agonist ^[94]
• Agomelatine – primarily a melatonin MT₁/MT₂ receptor agonist, with a less potent antagonism of 5-HT_2B and 5-HT_2C ^[95]
• AMAP102 (AMAP-102) – 5-HT_2B and 5-HT_2C antagonist ^{[74] [96]}
• Amesergide (LY-237733)
• Amisulpride
• Amitriptyline
• Apomorphine
• Aripiprazole ^[34]
• Asenapine ^[34]
• BMB-201 – and active form BMB-39a ^[97]
• Brexpiprazole
• Brilaroxazine
• C-122 ^{[74] [34]}
• Cariprazine ^{[34] [98]}
• Chlorpromazine
• Clozapine ^{[67] [34]}
• Cyproheptadine
• Desmethylclozapine (NDMC; norclozapine)
• Ibogainalog ^[99]
• ITI-1549 ^[100]
• KB-128 – 5-HT_2A and 5-HT_2B antagonist and 5-HT_2C agonist ^[101]
• Lisuride – a dopamine agonist of the ergoline class, that is also a 5-HT_2B antagonist ^[102] and a dual 5-HT_2A/C agonist ^[103]
• Lurasidone
• LY-53857
• Mesulergine ^[67]
• Metadoxine – a 5-HT_2B antagonist and GABA-activity modulator ^[104]
• Metergoline ^[67]
• Metitepine (methiothepin) ^[67]
• Mianserin ^[67]
• Molindone ^{[105] [106]}
• N-Methylamisulpride
• Nantenine ^[74]
• Naphthylpiperazine (1-NP)
• Olanzapine
• Pimethixene ^[77]
• Pipamperone
• Pizotifen (pizotyline)
• Promethazine ^[107]
• Quetiapine
• Rauwolscine ^[34]
• Risperidone
• Ritanserin ^{[34] [67]}
• SB-200,646 – 5-HT_2B/5-HT_2C antagonist, selective over 5-HT_2A
• SB-206,553 – mixed 5-HT_2B and 5-HT_2C antagonist and PAM at α₇ nAChR ^{[76] [108] [109] [67]}
• SB-221,284 – 5-HT_2B/5-HT_2C antagonist ^{[38] [67]}
• SB-228,357 – 5-HT_2B/5-HT_2C antagonist
• SDZ SER-082 – a mixed 5-HT_2B/C antagonist
• Spiperone
• Tabernanthalog (TBG; DLX-007) ^[99]
• Tegaserod – primarily a 5-HT₄ agonist, but also a 5-HT_2B antagonist ^{[110] [111]}
• Terguride – an oral, potent antagonist of 5-HT_2A and 5-HT_2B receptors ^{[76] [34]}
• Trazodone ^[67]
• Vabicaserin ^[112]
• Viloxazine – weak 5-HT_2B antagonist and 5-HT_2C agonist ^{[113] [114]}
• Xanomeline – similar affinity as for muscarinic acetylcholine receptors ^{[91] [115] [116]}
• Yohimbine ^[34]
• Zalsupindole (DLX-001; AAZ-A-154) ^[117]
• Ziprasidone

Unknown or unsorted selectivity

• AM1030 (AM-1030) ^{[74] [118]}

Peripherally selective

• Sarpogrelate (MCI-9042, LS-187,118) – non-selective 5-HT₂ antagonist, but ~2 orders of magnitude lower affinity at 5-HT_2B than at 5-HT_2A ^{[119] [120]}
• VU0530244 – 5-HT_2B-selective ^[121]
• VU0631019 – 5-HT_2B-selective ^[121]
• VU6055320 – 5-HT_2B-selective ^{[91] [92]}

BW-501C67 and xylamidine are known peripherally selective antagonists of the serotonin 5-HT₂ receptors, including of the serotonin 5-HT_2A and 5-HT_2B receptors, but their serotonin 5-HT_2B receptor interactions do not appear to have been described. ^{[122] [123] [124]}

Possible applications

5-HT_2B 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. ^[125] More recent research has focused on possible application of 5-HT_2B antagonists as treatments for chronic heart disease. ^{[126] [127]} Research claims serotonin 5-HT_2B receptors have effect on liver regeneration. ^[128] Antagonism of 5-HT_2B may attenuate fibrogenesis and improve liver function in disease models in which fibrosis is pre-established and progressive.

See also

• 5-HT receptor

References

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Further reading

• 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. Bibcode:1994FEBSL.352..393C. 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. Bibcode:1994FEBSL.342...85S. 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

• "5-HT_2B". 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.