Disease relevance of HTR2B

• Chronic exposure to 5-HT can contribute to pulmonary hypertension through activation of constrictor 5-HT1B receptors and proliferative 5-HT2B receptors, and possibly through direct intracellular effects [1].
• Finally, we detected expression of the 5-HT2B receptor in spontaneous human and Mastomys natalensis carcinoid tumors and, similar to the 5-HT2B receptor transfected cells, the Mastomys tumor cells are also responsive to serotonin with similar coupling to p21ras activation [2].
• The selective 5-HT2C/2B receptor antagonist, SB-228357 (0.32-10 mg kg(-1) p.o.) significantly reversed haloperidol-induced catalepsy whereas the 5-HT2A and 5-HT2B receptor antagonists, MDL-100907 (0.003-0.1 mg kg(-1) p.o.) and SB-215505 (0.1-3.2 mg kg(-1) p.o.) respectively did not reverse haloperidol-induced catalepsy [3].
• Finally, this study reveals the antagonistic roles of 5-HT2A and 5-HT2B receptors in regulating the function of 5-HT1B/1D, a receptor involved in neuropsychiatric disorders and migraine pathogenesis [4].
• BW 723C86, a 5-HT2B receptor agonist, causes hyperphagia and reduced grooming in rats [5].

Psychiatry related information on HTR2B

• Here we describe a genome-scan with 391 simple sequence repeat markers in 300 Caucasians, identifying HTR2B gene as a candidate for drug abuse vulnerability [6].
• The serotonin receptor 2B gene (HTR2B; MIM 601122) is a pharmacological and positional candidate gene in early-onset obsessive-compulsive disorder [7].
• The recent development of selective ligands and knockout mice for other 5-HT receptors, including the 5-HT2B and 5-HT6 receptors, has also suggested a role for these receptor subtypes in eating behavior [8].
• Increased wakefulness, motor activity and decreased theta activity after blockade of the 5-HT2B receptor by the subtype-selective antagonist SB-215505 [9].

High impact information on HTR2B

• 5-HT2B receptor-mediated serotonin morphogenetic functions in mouse cranial neural crest and myocardiac cells [10].
• In addition, whole mount in situ hybridisation and immunohistochemistry on similar stage embryos detected 5-HT2B expression in neural crest cells, heart myocardium and somites [10].
• The serotonin binding site of human and murine 5-HT2B receptors: molecular modeling and site-directed mutagenesis [11].
• 5-HT1B/1D and 5-HT2B receptors are expressed since day 2 of the serotonergic differentiation while 5-HT2A receptors are induced at day 4 [4].
• In addition to this mitogenic action, transforming activity of serotonin is mediated by the 5-HT2B receptor since its expression in LMTK- cells is absolutely required for foci formation and for these foci to form tumors in nude mice [2].

Chemical compound and disease context of HTR2B

• Our review of the literature strongly suggests that m-CPP and fenfluramine provoke migraine attacks by stimulating, directly or indirectly, the 5HT2C/5HT2B receptors, although there is no total agreement with this interpretation [12].
• 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 [13].
• MT-500 (formerly RS-127445) is a 5-HT2B antagonist being developed for the prophylactic treatment of migraine [14].

Biological context of HTR2B

• Sequences of a putative promoter region and splice regions were first elucidated, then sequenced along with HTR2B coding regions [7].
• Probands from seven families included in a previous genome scan in which one of the strongest linkage findings was to a region including HTR2B, along with two genomic DNA pools of 10 unrelated control subjects and 10 unrelated autism probands were screened [7].
• We also found novel isoforms for MT2, MRR, and 5HT2B and documented the process of RNA editing for 5HT2C [15].
• The 5-HT2B receptor has been shown to couple to phosphoinositide hydrolysis as do the other two members of this subfamily when expressed in AV12-664 cells [16].
• 2. PCR amplification was used to determine the tissue distribution of human 5-HT2B receptor mRNA. mRNA encoding the 5-HT2B receptor was expressed with greatest abundance in human liver and kidney [17].

Anatomical context of HTR2B

• 4. The human 5-HT2B receptor was expressed in Cos-7 cells and its ligand binding characteristics were compared to similarly expressed human 5-HT2A and 5-HT2C receptors [17].
• Optic nerve tissue of 1-2 donors exhibited the presence of 5HT2B, 5HT5, and 5HT7 receptor mRNAs [18].
• 5HT2 receptor subtype mRNAs were the most abundant with 5HT2A and 5HT2B being the most predominant in the retina, ciliary body, ciliary epithelium, choroid, conjunctiva, and iris [18].
• Reverse transcription-polymerase chain reaction studies revealed human 5-HT2B receptor mRNA to be expressed in many tissues, including the central nervous system [19].
• Based on distribution studies of 5-HT2B receptor mRNA, human uterus cDNA libraries were constructed and screened, resulting in the isolation of several full-length cDNA clones [19].

Associations of HTR2B with chemical compounds

• OBJECTIVE AND METHODS: 5-Hydroxytryptamine (serotonin) receptor 2B (HTR2B) is involved in brain development [6].
• On the basis of a higher affinity for ketanserin and a lower affinity for yohimbine the human 5-HT2B receptor also appeared to differ from the rat 5-HT2B receptor.(ABSTRACT TRUNCATED AT 250 WORDS)[17]
• The ligand specificity of the human 5-HT2B receptor (5-HT > ritanserin > SB 204741 > spiperone) was distinct from that of the human 5-HT2A (ritanserin > spiperone > 5-HT > SB 204741) and 5-HT2C (ritanserin > 5-HT > spiperone = SB 204741) receptors [17].
• The agonist-induced [Ca2+]i mobilization in h-CM cells was potently blocked by the 5-HT2A-selective antagonist M-100907 (IC50=1.2+/-0.4 nM) but less potently by the antagonists for 5-HT2B (RS-127445, IC50>10 microM) and 5-HT2C (RS-102221, IC50=5.8+/-2.3 microM) receptors [20].
• Cortical perfusion with M100907, or the atypical antipsychotic drug risperidone, but not the 5-HT2B/C ligand SB 206553, also decreased dopamine release induced physiologically by stress [21].

Regulatory relationships of HTR2B

• 1. SB 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2 ,3-f]indole) displays a high affinity (pK1 7.9) for the cloned human 5-HT2C receptor expressed in HEK 293 cells and the 5-HT2B receptor (pA2 8.9) as measured in the rat stomach fundus preparation [22].
• Mechanisms intrinsic to 5-HT2B receptor-induced potentiation of NMDA receptor responses in frog motoneurones [23].

Other interactions of HTR2B

• RESULTS: h-TM cells expressed robust mRNA signals for 5HT2A and 5HT2B receptors [24].
• The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo [25].
• More specifically, the recent finding that the 5-HT2B/2C receptor agonist, 1-(m-chlorophenyl)-piperazine (mCPP) is anticonvulsant has kindled an interest into the investigation of the serotonergic 5-HT2C receptor subtype as a potential target for the treatment of epilepsy [26].
• Isolated or clustered small neuroendocrine cells without atypia expressing chromogranin A, somatostatin and/or glucagon, serotonin (5-HT) and, the 5-HT2B receptors [27].
• Recent findings have implicated the 5-hydroxytryptamine 2B (5-HT2B) serotonin receptor in mediating the heart valve fibroplasia [valvular heart disease (VHD)] and primary pulmonary hypertension observed in patients taking the now-banned appetite suppressant fenfluramine (Pondimin, Redux) [28].

Analytical, diagnostic and therapeutic context of HTR2B

• 3. Northern blot analysis confirmed the presence of 5-HT2B receptor mRNA (a 2.4 kB sized band) in pancreas, liver and kidney [17].
• RESULTS: By RT-PCR, 5-HT1b, 5-HT2A and 5-HT2B mRNAs were detected in all of the 14 patients [29].
• As chronic fluoxetine and paroxetine did not reduce brain mCPP levels (determined by HPLC 30 min after 4 mg/kg i.p.) the results suggest that chronic SSRI's, but not desipramine, reduce 5-HT2C/5-HT2B receptor responsivity [30].

References