Disease relevance of HTR1B

• In primary lung cancers, decreased mRNA expression of HTR1B was observed in 11 of 20 cases, and that of EDN1 was in 16 of 20 cases [1].
• 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 [2].
• Both 5-HT1B and 5-HT2A receptors can mediate coronary artery spasm but only 5-HT1B receptors appear involved in coronary spasm of patients treated with triptans or with Prinzmetal angina [2].
• Further studies on 5-HT1B/ID receptors will thus give new insights into the foetal development and pathophysiology of pre-eclampsia [3].
• 1. 311C90 (zolmitriptan zomig: (S)-4[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone) is a novel 5-HT1B/1D receptor agonist with proven efficacy in the acute treatment of migraine [4].

Psychiatry related information on HTR1B

• Polymorphisms of the HTR1B gene have been implicated in a variety of psychiatric disorders including attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) [5].
• The objectives of this study were to: (i) expand our original investigation of the relationship between the HTR1B receptor gene and attention deficit/hyperactivity and; (ii) to investigate a possible association of obsessive behaviors/perfectionism and the HTR1B gene in a sample of 203 families with an ADHD proband [5].
• Serotonin 5-HT1A, 5-HT1B, and 5-HT2A receptor mRNA expression in subjects with major depression, bipolar disorder, and schizophrenia [6].
• Substance abuse disorder and major depression are associated with the human 5-HT1B receptor gene (HTR1B) G861C polymorphism [7].
• The 5-HT1B receptor gene has been postulated to play a modulatory role in alcohol consumption and alcohol dependence, and was considered a candidate gene for alcoholism [8].

High impact information on HTR1B

• Techniques to augment signaling by neurochemical mediators of leptin action that lie downstream of at least some levels of obesity-associated leptin resistance include activation of melanocortin receptors or 5-HT2C and 5-HT1B receptors [9].
• In doing so, they advocate that the so-called '5-HT1-like' receptors, having been shown to be a heterogeneous population of 5-HT1B, 5-HT1D and 5-HT7 receptors, are now redundant [10].
• We therefore investigated whether the 5-HT1B gene (HTR1B) is linked to alcoholism with aggressive and impulsive behavior in the human, as represented by 2 psychiatric diagnoses: antisocial personality disorder and intermittent explosive disorder comorbid with alcoholism [11].
• Human 5-HT1A sites can be distinguished from human 5-HT1B, 5-HT2, and 5-HT3 sites and from equivalent sites in rat and bovine cortex [12].
• Among these receptors, the 5-HT1B subtypes play a particular role as they are autoreceptors located on 5-HT neurons terminals and heteroreceptors located on non-serotonergic terminals where they control the release of the neurotransmitter [13].

Chemical compound and disease context of HTR1B

• Stimulus generalization occurs among these agents regardless of which is used as the training drug, although stimulus generalization does not occur with 5-HT1A-selective agonists [e.g., 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT)] or with 5-HT1B-selective agonists [e.g., 1-(3-trifluoromethylphenyl)piperazine (TFMPP)] [14].
• CONCLUSIONS: Eletriptan, a 5HT1B/1D-agonist effective in migraine, causes no significant coronary artery constriction in patients without significant obstructive coronary artery disease [15].
• Human 5-HT1B and 5-HT1D receptors have been implicated as molecular targets for the treatment of acute migraine based upon the pharmacological actions and clinical efficacy of sumatriptan, an agonist for human 5-HT1B/1D receptors [16].
• 1. Alniditan, a novel migraine abortive agent, is a potent 5-HT1B/5-HT1D receptor agonist of nM affinity [17].
• F 11356, a novel 5-hydroxytryptamine (5-HT) derivative with potent, selective, and unique high intrinsic activity at 5-HT1B/1D receptors in models relevant to migraine [18].

Biological context of HTR1B

• Our results indicate that HTR1B is the target of substantial transcriptional genetic regulation by common haplotypes, which are in LD with the HTR1B single-nucleotide polymorphism (SNP) most commonly used in association studies [19].
• Computational analysis of the HTR1B gene predicted that a 5' segment, spanning common DNA sequence variations, T-261G, A-161T, and -182INS/DEL-181, contained a putative functional promoter [19].
• MS-RDA was shown to isolate DNA fragments that are hypermethylated and silenced, such as HTR1B, and those whose expressions are altered and the methylation statuses outside the promoter region are altered, such as EDN1 [1].
• We systematically and comprehensively investigated polymorphisms of the HTR1B gene as well as their linkage disequilibrium and ancestral relationships [20].
• Evidence for an association between the HTR1B gene and ADHD as a qualitative diagnosis, or the inattentive and hyperactive-impulsive quantitative traits was not supported by either TDT single marker analysis or haplotype analysis [5].

Anatomical context of HTR1B

• By RT-PCR of the five genes in the carcinoma cell lines and NHBE, decreased expression of HTR1B (5-hydroxytryptamine receptor 1B) and EDN1 (endothelin-1) was observed [1].
• 2. At the "5-HT1B-like' receptor mediating vascular contraction (rabbit saphenous vein), the compound was a potent (p[A50] = 6.79 +/- 0.06) partial agonist achieving 77 +/- 4% of the maximum effect to 5-hydroxytryptamine (5-HT) [4].
• 5-HT1B receptor-mediated contractions in human temporal artery: evidence from selective antagonists and 5-HT receptor mRNA expression [21].
• [3H]5-HT binding to transfected COS-7 cell membranes yields a pharmacological profile similar to that of 5-HT1B receptor [22].
• The magnitude of the 5-HT1B receptor responses is superior for sumatriptan and its dimer in rat compared to guinea-pig substantia nigra [23].

Associations of HTR1B with chemical compounds

• Demethylation and re-expression of HTR1B were observed after treatment of LK-2 cells with 5-aza-2'-deoxycytidine [1].
• Sequencing after bisulfite modification showed that the CpG island in the promoter region of HTR1B was hypermethylated, while that of EDN1 was not [1].
• Notably, SB-224289 at 1.0mg/kg potentiated a subeffective dose of the 5-HT1B/1D receptor agonist/antagonist mixed GR 127935, which facilitated learning consolidation and this effect was abolished by ketanserin at a higher dose [24].
• Two binding sites were detected in the presence of 1 microM pindolol (to block 5-HT1A and 5-HT1B receptors), and 100 nM mesulergine (to block 5-HT1C and 5-HT2 receptors) [25].
• METHODS: Segments of UCA and SFA were mounted in tissue baths and concentration-response curves to 5-HT and sumatriptan (5-HT1B/1D receptor agonist) were constructed in the absence or presence of ketanserin (5-HT2A receptor antagonist) or GR125743 (5-HT1B/1D receptor antagonist) [3].

Physical interactions of HTR1B

• We now report that Thr355Asn mutagenesis of the human 5-HT1D beta receptor alters the binding characteristics of the recombinant receptor in [3H]5-HT binding assays to a profile very similar to that of the rat 5-HT1B binding site [26].
• The antagonist radioligand [3H]GR125743 and the agonist radioligand [3H]5-HT were used to investigate the pharmacological characteristics of the G protein uncoupled agonist low-affinity and G protein coupled agonist high-affinity conformations of the wild-type and mutant human 5-hydroxytryptamine 1B (5-HT1B) receptors [27].

Regulatory relationships of HTR1B

• Accordingly, 5-hydroxytryptamine 1B receptor antagonists prevent G-proteinmediated inhibition of uptake in partially filled platelets and synaptic vesicles expressing VMAT2 [28].
• We identified a haplotype block encompassing HTR1B and performed haplotype and single-marker association analyses for the eight SNPs within or flanking this block in 229 families of ADHD probands [29].
• In acute migraine treatment, their mechanisms of action involve constricting the pain-producing intracranial extracerebral blood vessels at the 5-HT1B receptors and inhibiting the trigeminal neurotransmission at the peripheral and central 5-HT1D receptors [30].
• A comparative study with a C6-glial/pcDNA3/5-HT1B cell line expressing a similar amount of cloned human 5-HT1B receptors (Bmax: 360 fmol/mg protein) showed almost no intrinsic agonist activity for metergoline, 1-naphtylpiperazine and GR 127,935 [31].
• We have previously reported that the transfected Gi/Go protein-coupled human adenosine A1 receptor (expressed at 200 fmol/mg of protein) and the endogenous 5-HT1B receptor (not detectable using radioligand binding) suppress forskolin-stimulated cyclic AMP accumulation and stimulate increases in [Ca2+]i in Chinese hamster ovary cells (CHO) [32].

Other interactions of HTR1B

• Silencing of HTR1B and reduced expression of EDN1 in human lung cancers, revealed by methylation-sensitive representational difference analysis [1].
• In contrast, activation of 5-HT2A receptors with either 5-HT or (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane did not alter the 5-HT1B-like response [33].
• The reduction of 5-HT1B-like responsiveness produced by 5-HT2C receptor activation was independent of protein kinase C activation and increases in the intracellular calcium concentration [33].
• Similar studies on human cloned receptors confirmed that xanomeline is an agonist at human cloned 5-HT1A and 5-HT1B receptors [34].
• Metergoline and the selective 5-HT 1B/D receptor ligands GR 127935 as well as GR 125743 showed significant intrinsic activity (43% to 69%) at the 5-HT 1D receptor subtype, whereas the nonselective ligand 1-naphthylpiperazine yielded less (15% to 19%) intrinsic activity at both receptor subtypes [35].

Analytical, diagnostic and therapeutic context of HTR1B

• Acute vascular constriction by 5-HT is usually shared by 5-HT1B and 5-HT2A receptors, except in intracranial arteries which constrict only through 5-HT1B receptors [2].
• We report the molecular cloning of a fragment of human genomic DNA called S12, containing an open reading frame of 1170 nucleotides, which encodes a receptor for serotonin of 390 amino acids [36].
• Contractile 5-HT1B receptors in human cerebral arteries: pharmacological characterization and localization with immunocytochemistry [37].
• 4. RT - PCR confirmed the presence of substantial amounts of mRNA for the 5-HT2A and 5-HT1B receptor subtypes in these arteries whilst only trace amounts of 5-HT1D receptor message were evident [38].
• Polymorphism of the serotonin 5-HT1B receptor gene (HTR1B) associated with minimum lifetime body mass index in women with bulimia nervosa [39].

References