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5-HT7receptor

From Wikipedia, the free encyclopedia
HTR7
Identifiers
AliasesHTR7,5-HT7, 5-HT7 receptor, 5-hydroxytryptamine receptor 7
External IDsOMIM:182137;MGI:99841;HomoloGene:20244;GeneCards:HTR7;OMA:HTR7 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3363

15566

Ensembl

ENSG00000148680

ENSMUSG00000024798

UniProt

P34969

P32304

RefSeq (mRNA)

NM_019860
NM_000872
NM_019859

RefSeq (protein)

NP_000863
NP_062873
NP_062874

Location (UCSC)Chr 10: 90.74 – 90.86 MbChr 19: 35.94 – 36.03 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The5-HT7receptoris a member of theGPCRsuperfamily of cell surfacereceptorsand is activated by theneurotransmitterserotonin(5-hydroxytryptamine, 5-HT).[5]The 5-HT7receptor is coupled toGs(stimulates the production of the intracellular signaling moleculecAMP)[6][7]and is expressed in a variety of human tissues, particularly in the brain, the gastrointestinal tract, and in various blood vessels.[7]This receptor has been a drug development target for the treatment of several clinical disorders.[8]The 5-HT7receptor is encoded by theHTR7gene,which in humans is transcribed into 3 different splice variants.[9]

Function

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When the 5-HT7receptor is activated by serotonin, it sets off a cascade of events starting with release of the stimulatoryG proteinGsfrom the GPCR complex. Gsin turn activatesadenylate cyclasewhich increasesintracellularlevels of thesecond messengercAMP.

The 5-HT7receptor plays a role insmooth musclerelaxationwithin thevasculatureand in thegastrointestinal tract.[5]The highest 5-HT7receptor densities are in thethalamusandhypothalamus,and it is present at higher densities also in thehippocampusandcortex.The 5-HT7receptor is involved inthermoregulation,circadian rhythm,learningandmemory,andsleep.Peripheral 5-HT7receptors are localized in enteric nerves; high levels of 5-HT7receptor-expressing mucosal nerve fibers were observed in the colon of patients withirritable bowel syndrome.An essential role of 5-HT7receptor in intestinalhyperalgesiawas demonstrated in mouse models withvisceral hypersensitivity,of which a novel 5-HT7receptor antagonist administered perorally reduced intestinal pain levels.[10]It is also speculated that this receptor may be involved inmoodregulation, suggesting that it may be a useful target in the treatment ofdepression.[11][12]

Variants

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Threesplice variantshave been identified in humans (designated h5-HT7(a),h5-HT7(b),and h5-HT7(d)), which encode receptors that differ in theircarboxy terminals.[9]The h5-HT7(a)is the full length receptor (445 amino acids),[7]while the h5-HT7(b)is truncated at amino acid 432 due to alternative splice donor site. The h5-HT7(d)is a distinct isoform of the receptor: the retention of an exon cassette in the region encoding the carboxyl terminal results a 479-amino acid receptor with a c-terminus markedly different from the h5-HT7(a).A 5-HT7(c)splice variant is detectable in rat tissue but is not expressed in humans. Conversely, rats do not express a splice variant homologous to the h5-HT7(d),as the rat 5-HT7gene lacks the exon necessary to encode this isoform.[9]Drug binding affinities are similar across the three human splice variants;[13]however, inverse agonist efficacies appear to differ between the splice variants.[14]

Discovery

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In 1983, evidence for a5-HT1-like receptor was first found.[15]Ten years later, 5-HT7receptor was cloned and characterized.[7]It has since become clear that the receptor described in 1983 is 5-HT7.[16]

Ligands

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Numerous orthosteric ligands of moderate to high affinity are known.Signaling biased ligandswere discovered and developed in 2018.[17]

Agonists

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Agonistsmimic the effects of the endogenous ligand, which is serotonin at the 5-HT7receptor (↑cAMP).

Antagonists

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Neutral antagonists(also known as silent antagonists) bind the receptor and have nointrinsic activitybut will block the activity of agonists or inverse agonists.Inverse agonistsinhibit theconstitutive activityof the receptor, producing functional effects opposite to those of agonists (at the 5-HT7receptor: ↓cAMP).[29][30]Neutral antagonists and inverse agonists are typically referred to collectively as "antagonists" and, in the case of the 5-HT7receptor, differentiation between neutral antagonists and inverse agonists is problematic due to differing levels of inverse agonist efficacy between receptor splice variants. For instance, mesulergine and metergoline are reported to be neutral antagonists at the h5-HT7(a)and h5-HT7(d)receptor isoforms but these drugs display marked inverse agonist effects at the h5-HT7(b)splice variant.[14]

Inactivating antagonists

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Inactivating antagonists are non-competitive antagonists that render the receptor persistently insensitive to agonist, which resembles receptor desensitization. Inactivation of the 5-HT7receptor, however, does not arise from the classically described mechanisms of receptor desensitization via receptor phosphorylation, beta-arrestin recruitment, and receptor internalization.[40]Inactivating antagonists all likely interact with the 5-HT7receptor in an irreversible/pseudo-irreversible manner, as is the case with [3H]risperidone.[41][42]

See also

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References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000148680–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000024798–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^abVanhoenacker P, Haegeman G, Leysen JE (February 2000). "5-HT7 receptors: current knowledge and future prospects".Trends in Pharmacological Sciences.21(2): 70–7.doi:10.1016/S0165-6147(99)01432-7.PMID10664612.
  6. ^Ruat M, Traiffort E, Leurs R, Tardivel-Lacombe J, Diaz J, Arrang JM, Schwartz JC (September 1993)."Molecular cloning, characterization, and localization of a high-affinity serotonin receptor (5-HT7) activating cAMP formation".Proceedings of the National Academy of Sciences of the United States of America.90(18): 8547–51.Bibcode:1993PNAS...90.8547R.doi:10.1073/pnas.90.18.8547.PMC47394.PMID8397408.
  7. ^abcdBard JA, Zgombick J, Adham N, Vaysse P, Branchek TA, Weinshank RL (November 1993)."Cloning of a novel human serotonin receptor (5-HT7) positively linked to adenylate cyclase".The Journal of Biological Chemistry.268(31): 23422–6.doi:10.1016/S0021-9258(19)49479-9.PMID8226867.
  8. ^Mnie-Filali O, Lambás-Señas L, Zimmer L, Haddjeri N (December 2007). "5-HT7 receptor antagonists as a new class of antidepressants".Drug News & Perspectives.20(10): 613–8.doi:10.1358/dnp.2007.20.10.1181354.PMID18301795.
  9. ^abcHeidmann DE, Metcalf MA, Kohen R, Hamblin MW (April 1997). "Four 5-hydroxytryptamine7 (5-HT7) receptor isoforms in human and rat produced by alternative splicing: species differences due to altered intron-exon organization".Journal of Neurochemistry.68(4): 1372–81.doi:10.1046/j.1471-4159.1997.68041372.x.PMID9084407.S2CID25951920.
  10. ^abChang WY, Yang YT, She MP, Tu CH, Lee TC, Wu MS, Sun CH, Hsin LW, Yu LC (2022)."5-HT 7 receptor-dependent intestinal neurite outgrowth contributes to visceral hypersensitivity in irritable bowel syndrome".Laboratory Investigation.102(9): 1023–1037.doi:10.1038/s41374-022-00800-z.PMC9420680.PMID35585132.
  11. ^Hedlund PB, Sutcliffe JG (September 2004). "Functional, molecular and pharmacological advances in 5-HT7 receptor research".Trends in Pharmacological Sciences.25(9): 481–6.doi:10.1016/j.tips.2004.07.002.PMID15559250.
  12. ^Naumenko VS, Popova NK, Lacivita E, Leopoldo M, Ponimaskin EG (July 2014)."Interplay between serotonin 5-HT1A and 5-HT7 receptors in depressive disorders".CNS Neuroscience & Therapeutics.20(7): 582–90.doi:10.1111/cns.12247.PMC6493079.PMID24935787.
  13. ^Krobert KA, Bach T, Syversveen T, Kvingedal AM, Levy FO (June 2001). "The cloned human 5-HT7 receptor splice variants: a comparative characterization of their pharmacology, function and distribution".Naunyn-Schmiedeberg's Archives of Pharmacology.363(6): 620–32.doi:10.1007/s002100000369.PMID11414657.S2CID21899516.
  14. ^abKrobert KA, Levy FO (March 2002)."The human 5-HT7 serotonin receptor splice variants: constitutive activity and inverse agonist effects".British Journal of Pharmacology.135(6): 1563–71.doi:10.1038/sj.bjp.0704588.PMC1573253.PMID11906971.
  15. ^Feniuk W, Humphrey PP, Watts AD (December 1983). "5-Hydroxytryptamine-induced relaxation of isolated mammalian smooth muscle".European Journal of Pharmacology.96(1–2): 71–8.doi:10.1016/0014-2999(83)90530-7.PMID6662198.
  16. ^Hoyer D, Hannon JP, Martin GR (April 2002). "Molecular, pharmacological and functional diversity of 5-HT receptors".Pharmacology Biochemistry and Behavior.71(4): 533–54.doi:10.1016/S0091-3057(01)00746-8.PMID11888546.S2CID25543069.
  17. ^Kim Y, Kim H, Lee J, Lee JK, Min SJ, Seong J, Rhim H, Tae J, Lee HJ, Choo H (August 2018). "Discovery of β-Arrestin Biased Ligands of 5-HT7R".J. Med. Chem.61(16): 7218–7233.doi:10.1021/acs.jmedchem.8b00642.PMID30028132.S2CID51700960.
  18. ^Sprouse J, Reynolds L, Li X, Braselton J, Schmidt A (January 2004). "8-OH-DPAT as a 5-HT7 agonist: phase shifts of the circadian biological clock through increases in cAMP production".Neuropharmacology.46(1): 52–62.doi:10.1016/j.neuropharm.2003.08.007.PMID14654097.S2CID41623573.
  19. ^Davies MA, Sheffler DJ,Roth BL.Aripiprazole: A Novel Atypical Antipsychotic Drug With a Uniquely Robust Pharmacology. CNS Drug Reviews [Internet]. 2004 [cited 2013 Aug 4];10(4):317–36. Available from:http://onlinelibrary.wiley /doi/10.1111/j.1527-3458.2004.tb00030.x/pdf
  20. ^Brenchat A, Ejarque M, Zamanillo D, Vela JM, Romero L (August 2011)."Potentiation of morphine analgesia by adjuvant activation of 5-HT7 receptors".Journal of Pharmacological Sciences.116(4): 388–91.doi:10.1254/jphs.11039sc.PMID21778664.
  21. ^Brenchat A, Nadal X, Romero L, Ovalle S, Muro A, Sánchez-Arroyos R, Portillo-Salido E, Pujol M, Montero A, Codony X, Burgueño J, Zamanillo D, Hamon M, Maldonado R, Vela JM (June 2010). "Pharmacological activation of 5-HT7 receptors reduces nerve injury-induced mechanical and thermal hypersensitivity".Pain.149(3): 483–94.doi:10.1016/j.pain.2010.03.007.PMID20399562.S2CID16613426.
  22. ^Brenchat A, Romero L, García M, Pujol M, Burgueño J, Torrens A, Hamon M, Baeyens JM, Buschmann H, Zamanillo D, Vela JM (February 2009). "5-HT7 receptor activation inhibits mechanical hypersensitivity secondary to capsaicin sensitization in mice".Pain.141(3): 239–47.doi:10.1016/j.pain.2008.11.009.PMID19118950.S2CID27144262.
  23. ^Powell SL, Gödecke T, Nikolic D, Chen SN, Ahn S, Dietz B, Farnsworth NR, van Breemen RB, Lankin DC, Pauli GF, Bolton JL (December 2008)."In vitro serotonergic activity of black cohosh and identification of N( Omega )-methylserotonin as a potential active constituent".Journal of Agricultural and Food Chemistry.56(24): 11718–26.doi:10.1021/jf803298z.PMC3684073.PMID19049296.
  24. ^Leopoldo M, Lacivita E, Contino M, Colabufo NA, Berardi F, Perrone R (August 2007). "Structure-activity relationship study on N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides, a class of 5-HT7 receptor agents. 2".Journal of Medicinal Chemistry.50(17): 4214–21.doi:10.1021/jm070487n.PMID17649988.
  25. ^Leopoldo M, Berardi F, Colabufo NA, Contino M, Lacivita E, Niso M, Perrone R, Tortorella V (December 2004). "Structure-affinity relationship study on N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinealkylamides, a new class of 5-hydroxytryptamine7 receptor agents".Journal of Medicinal Chemistry.47(26): 6616–24.doi:10.1021/jm049702f.PMID15588097.
  26. ^Hogendorf AS, Hogendorf A, Kurczab R, Satała G, Lenda T, Walczak M, Latacz G, Handzlik J, Kieć-Kononowicz K, Wierońska JM, Woźniak M, Cieślik P, Bugno R, Staroń J, Bojarski AJ (May 2017)."Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol".Scientific Reports.7(1444): 1444.Bibcode:2017NatSR...7.1444H.doi:10.1038/s41598-017-00822-4.PMC5431432.PMID28473721.
  27. ^Latacz G, Hogendorf AS, Hogendorf A, Lubelska A, Wierońska JM, Woźniak M, Cieślik P, Kieć-Kononowicz K, Handzlik J, Bojarski AJ (September 2018)."Search for a 5-CT alternative. In vitro and in vivo evaluation of novel pharmacological tools: 3-(1-alkyl-1H-imidazol-5-yl)-1H-indole-5-carboxamides, low-basicity 5-HT7 receptor agonists".MedChemComm.9(11): 1882–1890.doi:10.1039/c8md00313k.PMC6256855.PMID30568756.
  28. ^Hogendorf AS, Hogendorf A, Popiolek-Barczyk K, Ciechanowska A, Mika J, Satała G, Walczak M, Latacz G, Handzlik J, Kieć-Kononowicz K, Ponimaskin E, Schade S, Zeug A, Bijata M, Kubicki M, Kurczab R, Lenda T, Staroń J, Kurczab R, Satała G, Lenda T, Walczak M, Latacz G, Handzlik J, Kieć-Kononowicz K, Wierońska JM, Woźniak M, Cieślik P, Bugno R, Staroń J, Bugno R, Duszyńska B, Pilarski B, Bojarski AJ (2019). "Fluorinated indole-imidazole conjugates: Selective orally bioavailable 5-HT7 receptor low-basicity agonists, potential neuropathic painkillers".European Journal of Medicinal Chemistry.170:261–275.doi:10.1016/j.ejmech.2019.03.017.PMID30904783.S2CID85498356.
  29. ^Pittalà V, Salerno L, Modica M, Siracusa MA, Romeo G (September 2007). "5-HT7 receptor ligands: recent developments and potential therapeutic applications".Mini Reviews in Medicinal Chemistry.7(9): 945–60.doi:10.2174/138955707781662663.PMID17897083.
  30. ^Leopoldo M (March 2004). "Serotonin(7) receptors (5-HT(7)Rs) and their ligands".Current Medicinal Chemistry.11(5): 629–61.doi:10.2174/0929867043455828.PMID15032609.
  31. ^Volk B, Barkóczy J, Hegedus E, Udvari S, Gacsályi I, Mezei T, Pallagi K, Kompagne H, Lévay G, Egyed A, Hársing LG, Spedding M, Simig G (April 2008). "(Phenylpiperazinyl-butyl)oxindoles as selective 5-HT7 receptor antagonists".Journal of Medicinal Chemistry.51(8): 2522–32.doi:10.1021/jm070279v.PMID18361484.
  32. ^Abbas AI, Hedlund PB, Huang XP, Tran TB, Meltzer HY, Roth BL (July 2009)."Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo".Psychopharmacology.205(1): 119–28.doi:10.1007/s00213-009-1521-8.PMC2821721.PMID19337725.
  33. ^Ivachtchenko AV, Lavrovsky Y, Okun I (2016)."AVN-101: A Multi-Target Drug Candidate for the Treatment of CNS Disorders".J. Alzheimer's Dis.53(2): 583–620.doi:10.3233/JAD-151146.PMC4969713.PMID27232215.
  34. ^Lacivita E, Patarnello D, Stroth N, Caroli A, Niso M, Contino M, De Giorgio P, Di Pilato P, Colabufo NA, Berardi F, Perrone R, Svenningsson P, Hedlund PB, Leopoldo M (2012). "Investigations on the 1-(2-Biphenyl)piperazine Motif: Identification of New Potent and Selective Ligands for the Serotonin7 (5-HT7) Receptor with Agonist or Antagonist Action in Vitro or ex Vivo".Journal of Medicinal Chemistry.55(14): 6375–6380.doi:10.1021/jm3003679.PMID22738316.
  35. ^abRomero G, Pujol M, Pauwels PJ (October 2006). "Reanalysis of constitutively active rat and human 5-HT7(a) receptors in HEK-293F cells demonstrates lack of silent properties for reported neutral antagonists".Naunyn-Schmiedeberg's Archives of Pharmacology.374(1): 31–9.doi:10.1007/s00210-006-0093-y.PMID16967291.S2CID25203956.
  36. ^Forbes IT, Dabbs S, Duckworth DM, Jennings AJ, King FD, Lovell PJ, Brown AM, Collin L, Hagan JJ, Middlemiss DN, Riley GJ, Thomas DR, Upton N (February 1998). "(R)-3,N-dimethyl-N-[1-methyl-3-(4-methyl-piperidin-1-yl) propyl]benzenesulfonamide: the first selective 5-HT7 receptor antagonist".Journal of Medicinal Chemistry.41(5): 655–7.doi:10.1021/jm970519e.PMID9513592.
  37. ^abMahé C, Loetscher E, Feuerbach D, Müller W, Seiler MP, Schoeffter P (July 2004). "Differential inverse agonist efficacies of SB-258719, SB-258741 and SB-269970 at human recombinant serotonin 5-HT7 receptors".European Journal of Pharmacology.495(2–3): 97–102.doi:10.1016/j.ejphar.2004.05.033.PMID15249157.
  38. ^Lovell PJ, Bromidge SM, Dabbs S, Duckworth DM, Forbes IT, Jennings AJ, King FD, Middlemiss DN, Rahman SK, Saunders DV, Collin LL, Hagan JJ, Riley GJ, Thomas DR (February 2000). "A novel, potent, and selective 5-HT(7) antagonist: (R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)pyrrolidine-1-sulfonyl) phen ol (SB-269970)".Journal of Medicinal Chemistry.43(3): 342–5.doi:10.1021/jm991151j.PMID10669560.
  39. ^Forbes IT, Douglas S, Gribble AD, Ife RJ, Lightfoot AP, Garner AE, Riley GJ, Jeffrey P, Stevens AJ, Stean TO, Thomas DR (November 2002). "SB-656104-A: a novel 5-HT(7) receptor antagonist with improved in vivo properties".Bioorganic & Medicinal Chemistry Letters.12(22): 3341–4.doi:10.1016/S0960-894X(02)00690-X.PMID12392747.
  40. ^Zhang J, Ferguson SS, Barak LS, Aber MJ, Giros B, Lefkowitz RJ, Caron MG (1997). "Molecular mechanisms of G protein-coupled receptor signaling: role of G protein-coupled receptor kinases and arrestins in receptor desensitization and resensitization".Receptors & Channels.5(3–4): 193–9.PMID9606723.
  41. ^abcdSmith C, Rahman T, Toohey N, Mazurkiewicz J, Herrick-Davis K, Teitler M (October 2006). "Risperidone irreversibly binds to and inactivates the h5-HT7 serotonin receptor".Molecular Pharmacology.70(4): 1264–70.doi:10.1124/mol.106.024612.PMID16870886.S2CID1678887.
  42. ^abcdKnight JA, Smith C, Toohey N, Klein MT, Teitler M (February 2009)."Pharmacological analysis of the novel, rapid, and potent inactivation of the human 5-Hydroxytryptamine7 receptor by risperidone, 9-OH-Risperidone, and other inactivating antagonists".Molecular Pharmacology.75(2): 374–80.doi:10.1124/mol.108.052084.PMC2671286.PMID18996971.
[edit]
  • "5-HT7".IUPHAR Database of Receptors and Ion Channels.International Union of Basic and Clinical Pharmacology.
  • HumanHTR7genome location andHTR7gene details page in theUCSC Genome Browser.

This article incorporates text from theUnited States National Library of Medicine,which is in thepublic domain.

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