5-HT1B receptor explained

5-hydroxytryptamine receptor 1B also known as the 5-HT_1B receptor is a protein that in humans is encoded by the HTR1B gene.^{[1] [2]} The 5-HT_1B receptor is a 5-HT receptor subtype.^[3]

Tissue distribution and function

5-HT_1B receptors are widely distributed throughout the central nervous system with the highest concentrations found in the frontal cortex, basal ganglia, striatum, and the hippocampus.^[4] The function of the 5-HT_1B receptor differs depending upon its location. In the frontal cortex, it is believed to act as a terminal receptor inhibiting the release of dopamine. In the basal ganglia and the striatum, evidence suggests 5-HT signaling acts on an autoreceptor, inhibiting the release of serotonin^[5] and decreasing glutamatergic transmission by reducing miniature excitatory postsynaptic potential (mEPSP) frequency,^[6] respectively. In the hippocampus, a recent study has demonstrated that activation of postsynaptic 5-HT_1B heteroreceptors produces a facilitation in excitatory synaptic transmission which is altered in depression.^[7] When the expression of 5-HT_1B in human cortex was traced throughout life, significant changes during adolescence were observed, in a way that is strongly correlated with the expression of 5-HT_1E.^[8]

Outside of the CNS, the 5-HT_1B receptor is also expressed on the endothelium of blood vessels, particularly in the meninges.^[9] Activation of these receptors results in vasoconstriction. The high distribution of vasoconstrictive 5-HT_1B and 5-HT_1D receptors around the brain makes them a valuable drug target for the treatment of migraines.

Blocking 5-HT_1B receptor signalling also increases the number of osteoblasts, bone mass, and the bone formation rate.^[10]

Knockout mice lacking the 5-HT_1B gene have been reported to have a higher preference for alcohol, although later studies failed to replicate such abnormalities in alcohol consumption.^[11] These mice have also been reported to have a lower measure of anxiety (such as on the elevated plus maze test) and a higher measure of aggression.

Under basal conditions, knockout mice present with a "normal" phenotype and exhibit a sucrose preference (lack of sucrose preference is considered a measure of anhedonia). However, after undergoing chronic unpredictable stress treatment to induce a "depression-like" phenotype these animals do not benefit from administration of selective serotonin reuptake inhibitor (SSRIs).

Ligands

Agonists

• Ergotamine (vasoconstrictor in migraine)
• Oxymetazoline
• Sumatriptan (vasoconstrictor in migraine)
• Zolmitriptan
• 5-Carboxamidotryptamine
• CGS-12066A
• CP-93,129 (peripherally acting)
• CP-94,253
• CP-122,288 (mixed 5-HT_1B/1D agonist)
• CP-135,807 (mixed 5-HT_1B/1D agonist)
• RU-24969 (mixed 5-HT_1A/1B agonist)

Partial agonists

• Ziprasidone (antipsychotic)
• Asenapine (antipsychotic)
• Vortioxetine (antidepressant)

Antagonists and inverse agonists

• Methiothepin (antipsychotic)
• Yohimbine (aphrodisiac)
• Metergoline
  • Aripiprazole Isamoltane
• AR-A000002^[12]
• SB-216,641
• SB-224,289 (inverse agonist)^[13]
• SB-236,057 (inverse agonist)^[14]

Undetermined Action

• Dextromethorphan (Cough Suppressant)^[15]

Genetics

In humans the protein is coded by the gene HTR1B.

A genetic variant in the promoter region, A-161T, has been examined with respect to personality traits and showed no major effect.^[16]

See also

• 5-HT₁ receptor
• 5-HT receptor

Further reading

• Olivier B, van Oorschot R . 5-HT1B receptors and aggression: a review . European Journal of Pharmacology . 526 . 1–3 . 207–17 . Dec 2005 . 16310769 . 10.1016/j.ejphar.2005.09.066 .
• Hamblin MW, Metcalf MA, McGuffin RW, Karpells S . Molecular cloning and functional characterization of a human 5-HT1B serotonin receptor: a homologue of the rat 5-HT1B receptor with 5-HT1D-like pharmacological specificity . Biochemical and Biophysical Research Communications . 184 . 2 . 752–9 . Apr 1992 . 1315531 . 10.1016/0006-291X(92)90654-4 .
• Veldman SA, Bienkowski MJ . Cloning and pharmacological characterization of a novel human 5-hydroxytryptamine1D receptor subtype . Molecular Pharmacology . 42 . 3 . 439–44 . Sep 1992 . 1328844 .
• Demchyshyn L, Sunahara RK, Miller K, Teitler M, Hoffman BJ, Kennedy JL, Seeman P, Van Tol HH, Niznik HB . A human serotonin 1D receptor variant (5HT1D beta) encoded by an intronless gene on chromosome 6 . Proceedings of the National Academy of Sciences of the United States of America . 89 . 12 . 5522–6 . Jun 1992 . 1351684 . 49324 . 10.1073/pnas.89.12.5522 . 1992PNAS...89.5522D . free .
• Levy FO, Gudermann T, Perez-Reyes E, Birnbaumer M, Kaumann AJ, Birnbaumer L . Molecular cloning of a human serotonin receptor (S12) with a pharmacological profile resembling that of the 5-HT1D subtype . The Journal of Biological Chemistry . 267 . 11 . 7553–62 . Apr 1992 . 10.1016/S0021-9258(18)42552-5 . 1559993 . free .
• Weinshank RL, Zgombick JM, Macchi MJ, Branchek TA, Hartig PR . Human serotonin 1D receptor is encoded by a subfamily of two distinct genes: 5-HT1D alpha and 5-HT1D beta . Proceedings of the National Academy of Sciences of the United States of America . 89 . 8 . 3630–4 . Apr 1992 . 1565658 . 48922 . 10.1073/pnas.89.8.3630 . 1992PNAS...89.3630W . free .
• Mochizuki D, Yuyama Y, Tsujita R, Komaki H, Sagai H . Cloning and expression of the human 5-HT1B-type receptor gene . Biochemical and Biophysical Research Communications . 185 . 2 . 517–23 . Jun 1992 . 1610347 . 10.1016/0006-291X(92)91655-A .
• Nöthen MM, Erdmann J, Shimron-Abarbanell D, Propping P . Identification of genetic variation in the human serotonin 1D beta receptor gene . Biochemical and Biophysical Research Communications . 205 . 2 . 1194–200 . Dec 1994 . 7802650 . 10.1006/bbrc.1994.2792 .
• Ng GY, George SR, Zastawny RL, Caron M, Bouvier M, Dennis M, O'Dowd BF . Human serotonin1B receptor expression in Sf9 cells: phosphorylation, palmitoylation, and adenylyl cyclase inhibition . Biochemistry . 32 . 43 . 11727–33 . Nov 1993 . 8218242 . 10.1021/bi00094a032 .
• Bouchelet I, Cohen Z, Case B, Séguéla P, Hamel E . Differential expression of sumatriptan-sensitive 5-hydroxytryptamine receptors in human trigeminal ganglia and cerebral blood vessels . Molecular Pharmacology . 50 . 2 . 219–23 . Aug 1996 . 8700126 .
• Varnäs K, Hall H, Bonaventure P, Sedvall G . Autoradiographic mapping of 5-HT(1B) and 5-HT(1D) receptors in the post mortem human brain using [(3)H]GR 125743 . Brain Research . 915 . 1 . 47–57 . Oct 2001 . 11578619 . 10.1016/S0006-8993(01)02823-2 . 43104381 .
• Salim K, Fenton T, Bacha J, Urien-Rodriguez H, Bonnert T, Skynner HA, Watts E, Kerby J, Heald A, Beer M, McAllister G, Guest PC . Oligomerization of G-protein-coupled receptors shown by selective co-immunoprecipitation . The Journal of Biological Chemistry . 277 . 18 . 15482–5 . May 2002 . 11854302 . 10.1074/jbc.M201539200 . free .
• Hasegawa Y, Higuchi S, Matsushita S, Miyaoka H . Association of a polymorphism of the serotonin 1B receptor gene and alcohol dependence with inactive aldehyde dehydrogenase-2 . Journal of Neural Transmission . 109 . 4 . 513–21 . Apr 2002 . 11956970 . 10.1007/s007020200042 . 35750034 .
• Hawi Z, Dring M, Kirley A, Foley D, Kent L, Craddock N, Asherson P, Curran S, Gould A, Richards S, Lawson D, Pay H, Turic D, Langley K, Owen M, O'Donovan M, Thapar A, Fitzgerald M, Gill M . Serotonergic system and attention deficit hyperactivity disorder (ADHD): a potential susceptibility locus at the 5-HT(1B) receptor gene in 273 nuclear families from a multi-centre sample . Molecular Psychiatry . 7 . 7 . 718–25 . 2003 . 12192616 . 10.1038/sj.mp.4001048 . free .
• Huang YY, Oquendo MA, Friedman JM, Greenhill LL, Brodsky B, Malone KM, Khait V, Mann JJ . Substance abuse disorder and major depression are associated with the human 5-HT1B receptor gene (HTR1B) G861C polymorphism . Neuropsychopharmacology . 28 . 1 . 163–9 . Jan 2003 . 12496953 . 10.1038/sj.npp.1300000 . free .
• Quist JF, Barr CL, Schachar R, Roberts W, Malone M, Tannock R, Basile VS, Beitchman J, Kennedy JL . The serotonin 5-HT1B receptor gene and attention deficit hyperactivity disorder . Molecular Psychiatry . 8 . 1 . 98–102 . Jan 2003 . 12556913 . 10.1038/sj.mp.4001244 . free .
• Sinha R, Cloninger CR, Parsian A . Linkage disequilibrium and haplotype analysis between serotonin receptor 1B gene variations and subtypes of alcoholism . American Journal of Medical Genetics Part B . 121B . 1 . 83–8 . Aug 2003 . 12898580 . 10.1002/ajmg.b.20064 . 33460360 .

External links

• Web site: 5-HT_1B . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology .

Notes and References

1. Jin H, Oksenberg D, Ashkenazi A, Peroutka SJ, Duncan AM, Rozmahel R, Yang Y, Mengod G, Palacios JM, O'Dowd BF . Characterization of the human 5-hydroxytryptamine1B receptor . The Journal of Biological Chemistry . 267 . 9 . 5735–8 . Mar 1992 . 10.1016/S0021-9258(18)42612-9 . 1348246 . free .
2. Sanders AR, Cao Q, Taylor J, Levin TE, Badner JA, Cravchik A, Comeron JM, Naruya S, Del Rosario A, Salvi DA, Walczyk KA, Mowry BJ, Levinson DF, Crowe RR, Silverman JM, Gejman PV . Genetic diversity of the human serotonin receptor 1B (HTR1B) gene . Genomics . 72 . 1 . 1–14 . Feb 2001 . 11247661 . 10.1006/geno.2000.6411 .
3. Web site: Entrez Gene: HTR1B 5-hydroxytryptamine (serotonin) receptor 1B.
4. Web site: 5-hydroxytryptamine (serotonin) receptor 1B, G protein-coupled. 23 Feb 2013.
5. Pytliak M, Vargová V, Mechírová V, Felšöci M . Serotonin receptors - from molecular biology to clinical applications . Physiological Research . 60 . 1 . 15–25 . 2011 . 20945968 . 10.33549/physiolres.931903 . free .
6. Huang CC, Yeh CM, Wu MY, Hsu KS . A single in vivo cocaine administration impairs 5-HT(1B) receptor-induced long-term depression in the nucleus accumbens . Journal of Neurochemistry . 125 . 6 . 809–21 . Jun 2013 . 23452061 . 10.1111/jnc.12227 . 45859780 . free .
7. Cai X, Kallarackal AJ, Kvarta MD, Goluskin S, Gaylor K, Bailey AM, Lee HK, Huganir RL, Thompson SM . Local potentiation of excitatory synapses by serotonin and its alteration in rodent models of depression . Nature Neuroscience . 16 . 4 . 464–72 . Apr 2013 . 23502536 . 10.1038/nn.3355 . 3609911.
8. Shoval G, Bar-Shira O, Zalsman G, John Mann J, Chechik G . Transitions in the transcriptome of the serotonergic and dopaminergic systems in the human brain during adolescence . European Neuropsychopharmacology . 24 . 7 . 1123–32 . Jul 2014 . 24721318 . 10.1016/j.euroneuro.2014.02.009 . 14534307 .
9. Tepper SJ, Rapoport AM, Sheftell FD . Mechanisms of action of the 5-HT1B/1D receptor agonists . Archives of Neurology . 59 . 7 . 1084–1088 . July 2002 . 12117355 . 10.1001/archneur.59.7.1084 . free .
10. Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schütz G, Glorieux FH, Chiang CY, Zajac JD, Insogna KL, Mann JJ, Hen R, Ducy P, Karsenty G . Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum . Cell . 135 . 5 . 825–37 . Nov 2008 . 19041748 . 2614332 . 10.1016/j.cell.2008.09.059.
11. Hoyer D, Hannon JP, Martin GR . Molecular, pharmacological and functional diversity of 5-HT receptors . Pharmacology Biochemistry and Behavior . 71 . 4 . 533–54 . Apr 2002 . 11888546 . 10.1016/S0091-3057(01)00746-8 . 25543069 .
12. Hudzik TJ, Yanek M, Porrey T, Evenden J, Paronis C, Mastrangelo M, Ryan C, Ross S, Stenfors C . Behavioral pharmacology of AR-A000002, a novel, selective 5-hydroxytryptamine(1B) antagonist . The Journal of Pharmacology and Experimental Therapeutics . 304 . 3 . 1072–84 . Mar 2003 . 12604684 . 10.1124/jpet.102.045468 . 20463714 .
13. Selkirk JV, Scott C, Ho M, Burton MJ, Watson J, Gaster LM, Collin L, Jones BJ, Middlemiss DN, Price GW . SB-224289--a novel selective (human) 5-HT1B receptor antagonist with negative intrinsic activity . British Journal of Pharmacology . 125 . 1 . 202–8 . Sep 1998 . 9776361 . 1565605 . 10.1038/sj.bjp.0702059 .
14. Roberts C, Watson J, Price GW, Middlemiss DN . SB-236057-A: a selective 5-HT1B receptor inverse agonist . CNS Drug Reviews . 7 . 4 . 433–44 . 2001 . 11830759 . 10.1111/j.1527-3458.2001.tb00209.x . 6741665 .
15. Nguyen L, Thomas KL, Lucke-Wold BP, Cavendish JZ, Crowe MS, Matsumoto RR. 2016. Dextromethorphan: An update on its utility for neurological and neuropsychiatric disorders. Pharmacol. Ther.. 159. 1–22. 26826604. 10.1016/j.pharmthera.2016.01.016.
16. Tsai SJ, Wang YC, Chen JY, Hong CJ . Allelic variants of the tryptophan hydroxylase (A218C) and serotonin 1B receptor (A-161T) and personality traits . Neuropsychobiology . 48 . 2 . 68–71 . 2003 . 14504413 . 10.1159/000072879 . 42559772 .