5-HT1A receptor

Из Википедије, слободне енциклопедије
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[уреди]

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[уреди]

Neuromodulacija[уреди]

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[уреди]

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[уреди]

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[уреди]

Antagonisti[уреди]

Genetika[уреди]

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[уреди]

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[уреди]

Literatura[уреди]

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  2. „Entrez Gene: HTR1A 5-hydroxytryptamine (serotonin) receptor 1A”. 
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Dodatna literatura[уреди]

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  • 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. doi:10.1017/S1461145704004845. PMID 15683551. 
  • Kalipatnapu S, Chattopadhyay A (2006). „Membrane protein solubilization: recent advances and challenges in solubilization of serotonin1A receptors”. IUBMB Life. 57 (7): 505—12. doi:10.1080/15216540500167237. PMID 16081372. 
  • 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 275657Слободан приступ. 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. doi:10.1016/0888-7543(91)90088-V. PMID 1685484. 
  • 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. doi:10.1093/nar/19.25.7155. PMC 332551Слободан приступ. PMID 1766875. 
  • 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. doi:10.1016/0888-7543(89)90138-9. PMID 2591972. 
  • 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. doi:10.1038/329075a0. PMID 3041227. 
  • 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. doi:10.1038/335358a0. PMID 3138543. 
  • 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. doi:10.1006/bbrc.1995.1692. PMID 7755630. 
  • 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. doi:10.1074/jbc.271.8.4417. PMID 8626793. 
  • 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. doi:10.1002/(SICI)1096-8628(19980907)81:5<434::AID-AJMG13>3.0.CO;2-D. PMID 9754630. 
  • 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. doi:10.1074/jbc.M201539200. PMID 11854302. 

Spoljašnje veze[уреди]

  • „5-HT1A. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.