5-HT1A receptor

Iz Wikipedije, slobodne enciklopedije
edit
5-hidroksitriptaminski (serotoninski) receptor 1A
Identifikatori
Simboli HTR1A; 5-HT1A; 5HT1a; ADRB2RL1; ADRBRL1
Vanjski ID OMIM109760 MGI96273 HomoloGene20148 IUPHAR: 5-HT1A GeneCards: HTR1A Gene
Pregled RNK izražavanja
PBB GE HTR1A 221351 at tn.png
podaci
Ortolozi
Vrsta Čovek Miš
Entrez 3350 15550
Ensembl ENSG00000178394 ENSMUSG00000021721
UniProt P08908 Q8BGS4
RefSeq (mRNA) NM_000524 NM_008308
RefSeq (protein) NP_000515 NP_032334
Lokacija (UCSC) Chr 5:
63.29 - 63.29 Mb
Chr 13:
106.56 - 106.57 Mb
PubMed pretraga [1] [2]

5-HT1A receptor je tip 5-HT receptora za koji se vezuje endogeni neurotransmiter serotonin (5-hidroksitriptamin, 5-HT). On je G protein-spregnuti receptor (GPCR) koji je spregnut sa Gi/Go i posreduje inhibitornu neurotransmisiju. Akronim HTR1A označava humani gen koji kodira ovaj receptor.[1][2]

Distribucija[uredi - уреди | uredi izvor]

5-HT1A receptor najšire rasprostranjen od svih 5-HT receptora. U centralnom nervnom sistemu, 5-HT1A receptori se nalaze u cerebralnom kortesu, hipokampusu, septumu, amigdali, i rafovom jezgru u visokim koncentracijama, dok su u manjim količinama takođe prisutni u bazalnoj gangliji i talamusu.[3][4][5]

Funkcija[uredi - уреди | uredi izvor]

Neuromodulacija[uredi - уреди | uredi izvor]

5-HT1A receptorski agonisti snižavaju krvni pritisak i brzinu srca centralnim mehanizmom, indukcijom periferne vazodilaticije, i stimulacijom vagus nerva.[6] Ti efekti su rezultat aktivacije 5-HT1A receptora u rostralnoj ventrolateralnoj meduli.[6] Simpatolitički antihipertenzivni lek urapidil je antagonist α1-adrenergičkog receptora i agonist α2-adrenergičkog receptora, kao i agonist 5-HT1A receptora. Poznato je da ova zadnja osobina doprinosi njegovim sveukupnom terapeutskom dejstvu.[7][8] Vazodilatacija krvnih sudova kože centralnom 5-HT1A aktivacijom povećava toplotnu disipaciju sa organizma u okolnu sredinu, posledica čega je sniženje telesne temperature.[9][10]

Aktivacija centralnih 5-HT1A receptora inicira oslobađanje ili inhibiciju norepinefrina u zavisnosti od vrste, verovatno iz locus coeruleus regiona, što zatim dovodi do redukcije ili povišenja neuronskog tona sfinkter mišića zenice modulacijom postsinaptičkih α2-adrenergički receptora unutar Edinger-Vestfalnog jezgra, što dovodi do dilatacije zenica kod glodara, i kontrakcije zenica kod primata uključujući ljude.[11][12][13]

Agonisti 5-HT1A receptora kao što su buspiron[14] i flesinoksan[15] su delotvorni u olakšavanju anksioznosti[16] i depresije.[17] Buspiron i tandospiron su trenutno odobreni za te indikacije u mnogim zemljama. Drugi, poput gepirona,[18] flesinoksana,[19] flibanserina,[20] i PRX-00023[21] su takođe bili ispitivani, mada još uvek nisu potpuno razvijeni i odobreni. Neki od atipičnih antipsihotika kao što je aripiprazol[22] su takođe parcijalni agonisti 5-HT1A receptora i ponekad se koriste u niskim dozama kao zamena za standardne antidepresive kao što su selektivni inhibitori preuzimanja serotonina (SSRI).[23]

Endokrinologija[uredi - уреди | uredi izvor]

Aktivacija 5-HT1A receptora indukuje sekreciju raznih hormona među kojima su kortizol, kortikosteron, adrenokortikotropni hormon (ACTH), oksitocin, prolaktin, hormon rasta, i β-endorfin.[24][25][26][27] Ovaj receptor ne utiče na sekreciju vazopresina ili renina, za razliku od 5-HT2 receptora.[24][28] Postoje indikacije da otpuštanje oksitocina doprinosi prosocijalnim, antiagresivnim i anksiolitičkim svojstvima primećenim nakon aktivacije receptora.[28] Moguće je da sekrecija β-endorfina doprinosi antidepresivnim, anksiolitičkim, i analgetskim efektima.

Ligandi[uredi - уреди | uredi izvor]

Distribucija 5-HT1A receptora u ljudskom mozgu može biti snimljena pozitronskom emisionom tomografijom koristeći radioligand [11C]WAY-100,635.[29] Na primer, u jednoj studiji je utvrđeno povećano 5-HT1A vezivanje kod tipa 2 dijabetesa.[30] Jedna druga PET studija je utvrdila negativnu korelaciju između stepena 5-HT1A vezivanja u rafijevom jezgru, hipokampusu i neokorteksu, i samo-prijavljene tendencije doživljavanja duhovnih iskustava.[31] Kad je obeležen sa tricijumom, WAY-100,635 može takođe da se koristi u autoradiografiji.[32]

Agonisti[uredi - уреди | uredi izvor]

Antagonisti[uredi - уреди | uredi izvor]

Genetika[uredi - уреди | uredi izvor]

5-HT1A receptor je kodiran HTR1A genom. Postoji više humanih polimorfizama vezanih za ovaj gen. Jedan pregled iz 2007. navodi 27 jednonukleotidnih polimorfizama (SNP).[33] Najviše istraženi su C-1019G (rs6295), C-1018G,[34] Ile28Val (rs1799921), Arg219Leu (rs1800044), i Gly22Ser (rs1799920).[33] Neki od preostalih SNP-ova su Pro16Leu, Gly272Asp, i sinonimni polimorfizam G294A (rs6294). Varijante ovog gena su bile studirane u vezi sa psihijatrijskim poremećajima, ali definitivni rezultati nisu dobijeni.[33]

Interakcije[uredi - уреди | uredi izvor]

Za 5-HT1A receptor je pokazano da interaguje sa moždanim neurotrofnim faktorom (BDNF), koji učestvuje u regulaciji raspoloženja i anksioznosti.[35][36] Pokazano je da ostvaruje interakcije sa sfingozin-1-fosfatnim receptorom 1 (S1PR1).[37]

Vidi još[uredi - уреди | uredi izvor]

Literatura[uredi - уреди | uredi izvor]

  1. Gilliam TC, Freimer NB, Kaufmann CA, Powchik PP, Bassett AS, Bengtsson U, Wasmuth JJ (November 1989). "Deletion mapping of DNA markers to a region of chromosome 5 that cosegregates with schizophrenia". Genomics 5 (4): 940–4. PMID 2591972. doi:10.1016/0888-7543(89)90138-9. 
  2. "Entrez Gene: HTR1A 5-hydroxytryptamine (serotonin) receptor 1A". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3350. 
  3. Ito H, Halldin C, Farde L. (1999). "Localization of 5-HT1A receptors in the living human brain using [carbonyl-11C]WAY-100635: PET with anatomic standardization technique.". J Nucl Med. 40 (1): 102–9. PMID 9935065. 
  4. Glennon RA, Dukat M, Westkaemper RB (1. 1. 2000.). "Serotonin Receptor Subtypes and Ligands". American College of Neurophyscopharmacology. http://www.acnp.org/g4/GN401000039/Ch039.html. pristupljeno 11. 4. 2008.. 
  5. de Almeida J, Mengod G. (2008). "Serotonin 1A receptors in human and monkey prefrontal cortex are mainly expressed in pyramidal neurons and in a GABAergic interneuron subpopulation: implications for schizophrenia and its treatment.". J Neurochem. 107 (2): 488–496. PMID 18761712. doi:10.1111/j.1471-4159.2008.05649.x. 
  6. 6,0 6,1 Dabiré H. (1991). "Central 5-hydroxytryptamine (5-HT) receptors in blood pressure regulation.". Therapie. 46 (6): 421–9. PMID 1819150. 
  7. Ramage AG (April 1991). "The mechanism of the sympathoinhibitory action of urapidil: role of 5-HT1A receptors". Br. J. Pharmacol. 102 (4): 998–1002. PMC 1917978. PMID 1855130. 
  8. Kolassa N, Beller KD, Sanders KH. (1989). "Involvement of brain 5-HT1A receptors in the hypotensive response to urapidil.". Am J Cardiol. 64 (7): 7D–10D. PMID 2569265. doi:10.1016/0002-9149(89)90688-7. 
  9. Ootsuka Y, Blessing WW. (2006). "Activation of 5-HT1A receptors in rostral medullary raphé inhibits cutaneous vasoconstriction elicited by cold exposure in rabbits.". Brain Res. 1073-1074: 252–61. PMID 16455061. doi:10.1016/j.brainres.2005.12.031. 
  10. Rusyniak DE, Zaretskaia MV, Zaretsky DV, DiMicco JA. (2007). "3,4-Methylenedioxymethamphetamine- and 8-hydroxy-2-di-n-propylamino-tetralin-induced hypothermia: role and location of 5-hydroxytryptamine 1A receptors.". J Pharmacol Exp Ther. 323 (2): 477–487. PMID 17702902. doi:10.1124/jpet.107.126169. 
  11. Yu Y, Ramage AG, Koss MC. (2004). "Pharmacological studies of 8-OH-DPAT-induced pupillary dilation in anesthetized rats.". Eur J Pharmacol. 489 (3): 207–213. PMID 15087245. doi:10.1016/j.ejphar.2004.03.007. 
  12. Prow MR, Martin KF, Heal DJ (1996). "8-OH-DPAT-induced mydriasis in mice: a pharmacological characterisation". Eur J Pharmacol. 317 (1): 21–8. PMID 8982715. doi:10.1016/S0014-2999(96)00693-0. 
  13. Fanciullacci M, Sicuteri R, Alessandri M, Geppetti P (March 1995). "Buspirone, but not sumatriptan, induces miosis in humans: relevance for a serotoninergic pupil control". Clinical Pharmacology and Therapeutics 57 (3): 349–55. PMID 7697953. doi:10.1016/0009-9236(95)90161-2. 
  14. Cohn, JB; Rickels K (1989). "A pooled, double-blind comparison of the effects of buspirone, diazepam and placebo in women with chronic anxiety". Curr Med Res Opin. 11 (5): 304–320. PMID 2649317. doi:10.1185/03007998909115213. 
  15. Cryan JF, Redmond AM, Kelly JP, Leonard BE. (1997). "The effects of the 5-HT1A agonist flesinoxan, in three paradigms for assessing antidepressant potential in the rat.". Eur Neuropsychopharmacol. 7 (2): 109–114. PMID 9169298. doi:10.1016/S0924-977X(96)00391-4. 
  16. Parks CL, Robinson PS, Sibille E, Shenk T, Toth M (1998). "Increased anxiety of mice lacking the serotonin1A receptor". Proc Natl Acad Sci U S A. 195 (18): 10734–9. PMC 27964. PMID 9724773. doi:10.1073/pnas.95.18.10734. 
  17. Kennett GA, Dourish CT, Curzon G (1987). "Antidepressant-like action of 5-HT1A agonists and conventional antidepressants in an animal model of depression". Eur J Pharmacol. 134 (3): 265–74. PMID 2883013. doi:10.1016/0014-2999(87)90357-8. 
  18. Keller MB, Ruwe FJ, Janssens CJ, Sitsen JM, Jokinen R, Janczewski J (February 2005). "Relapse prevention with gepirone ER in outpatients with major depression". Journal of Clinical Psychopharmacology 25 (1): 79–84. PMID 15643103. doi:10.1097/01.jcp.0000150221.53877.d9. 
  19. Cryan JF, Redmond AM, Kelly JP, Leonard BE (May 1997). "The effects of the 5-HT1A agonist flesinoxan, in three paradigms for assessing antidepressant potential in the rat". European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology 7 (2): 109–14. PMID 9169298. doi:10.1016/S0924-977X(96)00391-4. 
  20. Invernizzi RW, Sacchetti G, Parini S, Acconcia S, Samanin R (August 2003). "Flibanserin, a potential antidepressant drug, lowers 5-HT and raises dopamine and noradrenaline in the rat prefrontal cortex dialysate: role of 5-HT(1A) receptors.". Br J Pharmacol. 139 (7): 1281–8. PMC 1573953. PMID 12890707. doi:10.1038/sj.bjp.0705341. 
  21. de Paulis T. (2007). "Drug evaluation: PRX-00023, a selective 5-HT1A receptor agonist for depression.". Curr Opin Investig Drugs. 8 (1): 78–86. PMID 17263189. 
  22. Stark, AD et al. (2007). "Interaction of the novel antipsychotic aripiprazole with 5-HT1A and 5-HT2A receptors: functional receptor-binding and in vivo electrophysiological studies.". Psychopharmacology (Berl) 190 (3): 373–382. PMID 17242925. doi:10.1007/s00213-006-0621-y. 
  23. Vega, JAW; Mortimer AM, Tyson PJ (May 2003). "Conventional Antipsychotic Prescription in Unipolar Depression, I: An Audit and Recommendations for Practice". The Journal of Clinical Psychiatry (Physicians Postgraduate Press) 64 (5): 568–574. ISSN 1555-2101. PMID 12755661. doi:10.4088/JCP.v64n0512. Pristupljeno 2009-05-28. 
  24. 24,0 24,1 Van de Kar LD, Levy AD, Li Q, Brownfield MS. (1998). "A comparison of the oxytocin and vasopressin responses to the 5-HT1A agonist and potential anxiolytic drug alnespirone (S-20499)". Pharmacol Biochem Behav. 60 (3): 677–683. PMID 9678651. doi:10.1016/S0091-3057(98)00025-2. 
  25. Lorens SA, Van de Kar LD. (1987). "Differential effects of serotonin (5-HT1A and 5-HT2) agonists and antagonists on renin and corticosterone secretion". Neuroendocrinology. 45 (4): 305–310. PMID 2952898. doi:10.1159/000124754. 
  26. Koenig JI, Gudelsky GA, Meltzer HY. (1987). "Stimulation of corticosterone and beta-endorphin secretion in the rat by selective 5-HT receptor subtype activation". Eur J Pharmacol. 137 (1): 1–8. PMID 2956114. doi:10.1016/0014-2999(87)90175-0. 
  27. Pitchot W, Wauthy J, Legros JJ, Ansseau M (March 2004). "Hormonal and temperature responses to flesinoxan in normal volunteers: an antagonist study". European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology 14 (2): 151–5. PMID 15013031. doi:10.1016/S0924-977X(03)00108-1. 
  28. 28,0 28,1 Thompson MR, Callaghan PD, Hunt GE, Cornish JL, McGregor IS (May 2007). "A role for oxytocin and 5-HT(1A) receptors in the prosocial effects of 3,4 methylenedioxymethamphetamine ("ecstasy")". Neuroscience 146 (2): 509–14. PMID 17383105. doi:10.1016/j.neuroscience.2007.02.032. 
  29. Pike VW, McCarron JA, Lammerstma AA, Hume SP, Poole K, Grasby PM, Malizia A, Cliffe IA, Fletcher A, Bench CJ (1995). "First delineation of 5-HT1A receptors in human brain with PET and [11C]WAY-100635". Eur. J. Pharmacol. 283 (1–3): R1–3. PMID 7498295. doi:10.1016/0014-2999(95)00438-Q. 
  30. Price JC, Kelley DE, Ryan CM, Meltzer CC, Drevets WC, Mathis CA, Mazumdar S, Reynolds CF (2002). "Evidence of increased serotonin-1A receptor binding in type 2 diabetes: a positron emission tomography study". Brain Res. 927 (1): 97–103. PMID 11814436. doi:10.1016/S0006-8993(01)03297-8. 
  31. Borg J, Andrée B, Soderstrom H, Farde L (November 2003). "The serotonin system and spiritual experiences". Am J Psychiatry 160 (11): 1965–9. PMID 14594742. doi:10.1176/appi.ajp.160.11.1965. 
  32. Burnet PW, Eastwood SL, Harrison PJ (1997). "[3H]WAY-100635 for 5-HT1A receptor autoradiography in human brain: a comparison with [3H]8-OH-DPAT and demonstration of increased binding in the frontal cortex in schizophrenia". Neurochem. Int. 30 (6): 565–574. PMID 9152998. doi:10.1016/S0197-0186(96)00124-6. 
  33. 33,0 33,1 33,2 Drago A, Ronchi DD, Serretti A (August 2008). "5-HT1A gene variants and psychiatric disorders: a review of current literature and selection of SNPs for future studies". Int. J. Neuropsychopharmacol. 11 (5): 701–21. PMID 18047755. doi:10.1017/S1461145707008218. 
  34. Wu S, Comings DE (June 1999). "A common C-1018G polymorphism in the human 5-HT1A receptor gene". Psychiatr. Genet. 9 (2): 105–6. PMID 10412191. doi:10.1097/00041444-199906000-00010. 
  35. Anttila S, Huuhka K, Huuhka M, Rontu R, Hurme M, Leinonen E et al. (2007). "Interaction between 5-HT1A and BDNF genotypes increases the risk of treatment-resistant depression". J Neural Transm 114 (8): 1065–8. PMID 17401528. doi:10.1007/s00702-007-0705-9. 
  36. Guiard BP, David DJ, Deltheil T, Chenu F, Le Maître E, Renoir T et al. (2008). "Brain-derived neurotrophic factor-deficient mice exhibit a hippocampal hyperserotonergic phenotype". Int J Neuropsychopharmacol 11 (1): 79–92. PMID 17559709. doi:10.1017/S1461145707007857. 
  37. Salim, Kamran; Fenton Tim, Bacha Jamil, Urien-Rodriguez Hector, Bonnert Tim, Skynner Heather A, Watts Emma, Kerby Julie, Heald Anne, Beer Margaret, McAllister George, Guest Paul C (May 2002). "Oligomerization of G-protein-coupled receptors shown by selective co-immunoprecipitation". J. Biol. Chem. 277 (18): 15482–5. PMID 11854302. doi:10.1074/jbc.M201539200. 

Dodatna literatura[uredi - уреди | uredi izvor]

  • el Mestikawy S, Fargin A, Raymond JR et al. (1991). "The 5-HT1A receptor: an overview of recent advances". Neurochem. Res. 16 (1): 1–10. PMID 2052135. doi:10.1007/BF00965820. 
  • Hensler JG (2003). "Regulation of 5-HT1A receptor function in brain following agonist or antidepressant administration". Life Sci. 72 (15): 1665–82. PMID 12559389. doi:10.1016/S0024-3205(02)02482-7. 
  • Van Oekelen D, Luyten WH, Leysen JE (2003). "5-HT2A and 5-HT2C receptors and their atypical regulation properties". Life Sci. 72 (22): 2429–49. PMID 12650852. doi:10.1016/S0024-3205(03)00141-3. 
  • Lesch KP, Gutknecht L (2005). "Focus on The 5-HT1A receptor: emerging role of a gene regulatory variant in psychopathology and pharmacogenetics". Int. J. Neuropsychopharmacol. 7 (4): 381–5. PMID 15683551. doi:10.1017/S1461145704004845. 
  • Kalipatnapu S, Chattopadhyay A (2006). "Membrane protein solubilization: recent advances and challenges in solubilization of serotonin1A receptors". IUBMB Life 57 (7): 505–12. PMID 16081372. doi:10.1080/15216540500167237. 
  • Varrault A, Bockaert J, Waeber C (1992). "Activation of 5-HT1A receptors expressed in NIH-3T3 cells induces focus formation and potentiates EGF effect on DNA synthesis". Mol. Biol. Cell 3 (9): 961–9. PMC 275657. PMID 1330092. 
  • Levy FO, Gudermann T, Perez-Reyes E et al. (1992). "Molecular cloning of a human serotonin receptor (S12) with a pharmacological profile resembling that of the 5-HT1D subtype". J. Biol. Chem. 267 (11): 7553–62. PMID 1559993. 
  • Melmer G, Sherrington R, Mankoo B et al. (1992). "A cosmid clone for the 5HT1A receptor (HTR1A) reveals a TaqI RFLP that shows tight linkage to dna loci D5S6, D5S39, and D5S76". Genomics 11 (3): 767–9. PMID 1685484. doi:10.1016/0888-7543(91)90088-V. 
  • Parks CL, Chang LS, Shenk T (1992). "A polymerase chain reaction mediated by a single primer: cloning of genomic sequences adjacent to a serotonin receptor protein coding region". Nucleic Acids Res. 19 (25): 7155–60. PMC 332551. PMID 1766875. doi:10.1093/nar/19.25.7155. 
  • Gilliam TC, Freimer NB, Kaufmann CA et al. (1990). "Deletion mapping of DNA markers to a region of chromosome 5 that cosegregates with schizophrenia". Genomics 5 (4): 940–4. PMID 2591972. doi:10.1016/0888-7543(89)90138-9. 
  • Kobilka BK, Frielle T, Collins S et al. (1987). "An intronless gene encoding a potential member of the family of receptors coupled to guanine nucleotide regulatory proteins". Nature 329 (6134): 75–9. PMID 3041227. doi:10.1038/329075a0. 
  • Fargin A, Raymond JR, Lohse MJ et al. (1988). "The genomic clone G-21, which resembles a beta-adrenergic receptor sequence encodes the 5-HT1A receptor". Nature 335 (6188): 358–60. PMID 3138543. doi:10.1038/335358a0. 
  • Nakhai B, Nielsen DA, Linnoila M, Goldman D (1995). "Two naturally occurring amino acid substitutions in the human 5-HT1A receptor: glycine 22 to serine 22 and isoleucine 28 to valine 28". Biochem. Biophys. Res. Commun. 210 (2): 530–6. PMID 7755630. doi:10.1006/bbrc.1995.1692. 
  • Aune TM, McGrath KM, Sarr T et al. (1993). "Expression of 5HT1a receptors on activated human T cells. Regulation of cyclic AMP levels and T cell proliferation by 5-hydroxytryptamine". J. Immunol. 151 (3): 1175–83. PMID 8393041. 
  • Parks CL, Shenk T (1996). "The serotonin 1a receptor gene contains a TATA-less promoter that responds to MAZ and Sp1". J. Biol. Chem. 271 (8): 4417–30. PMID 8626793. doi:10.1074/jbc.271.8.4417. 
  • Stockmeier CA, Shapiro LA, Dilley GE et al. (1998). "Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression-postmortem evidence for decreased serotonin activity". J. Neurosci. 18 (18): 7394–401. PMID 9736659. 
  • Kawanishi Y, Harada S, Tachikawa H et al. (1998). "Novel mutations in the promoter and coding region of the human 5-HT1A receptor gene and association analysis in schizophrenia". Am. J. Med. Genet. 81 (5): 434–9. PMID 9754630. doi:10.1002/(SICI)1096-8628(19980907)81:5<434::AID-AJMG13>3.0.CO;2-D. 
  • Salim K, Fenton T, Bacha J et al. (2002). "Oligomerization of G-protein-coupled receptors shown by selective co-immunoprecipitation". J. Biol. Chem. 277 (18): 15482–5. PMID 11854302. doi:10.1074/jbc.M201539200. 

Spoljašnje veze[uredi - уреди | uredi izvor]