5-HT1A receptor

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5-hidroksitriptaminski (serotoninski) receptor 1A
Identifikatori
Simboli	HTR1A; 5-HT1A; 5HT1a; ADRB2RL1; ADRBRL1
Vanjski ID	OMIM: 109760 MGI: 96273 HomoloGene: 20148 IUPHAR: 5-HT1A GeneCards: HTR1A Gene
Ontologija gena Molekularna funkcija • aktivnost rodopsinu-sličnog receptora • receptorska aktivnost • serotoninska receptorska aktivnost Celularna komponenta • integralno sa ćelijskom membranom • membrana Biološki proces • prenos signala • signalni put G-protein spregnutog receptora • ponašanje • pozitivna regulacija ćelijske proliferacije
Pregled RNK izražavanja
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-HT_1A 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 G_i/G_o i posreduje inhibitornu neurotransmisiju. Akronim HTR1A označava humani gen koji kodira ovaj receptor.^[1][2]

Distribucija

5-HT_1A receptor najšire rasprostranjen od svih 5-HT receptora. U centralnom nervnom sistemu, 5-HT_1A 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

Neuromodulacija

5-HT_1A receptorski agonisti snižavaju krvni pritisak i brzinu srca centralnim mehanizmom, indukcijom periferne vazodilaticije, i stimulacijom vagus nerva.^[6] Ti efekti su rezultat aktivacije 5-HT_1A receptora u rostralnoj ventrolateralnoj meduli.^[6] Simpatolitički antihipertenzivni lek urapidil je antagonist α₁-adrenergičkog receptora i agonist α₂-adrenergičkog receptora, kao i agonist 5-HT_1A receptora. Poznato je da ova zadnja osobina doprinosi njegovim sveukupnom terapeutskom dejstvu.^[7][8] Vazodilatacija krvnih sudova kože centralnom 5-HT_1A aktivacijom povećava toplotnu disipaciju sa organizma u okolnu sredinu, posledica čega je sniženje telesne temperature.^[9][10]

Aktivacija centralnih 5-HT_1A 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-HT_1A 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-HT_1A receptora i ponekad se koriste u niskim dozama kao zamena za standardne antidepresive kao što su selektivni inhibitori preuzimanja serotonina (SSRI).^[23]

Endokrinologija

Aktivacija 5-HT_1A 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

Distribucija 5-HT_1A 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-HT_1A vezivanje kod tipa 2 dijabetesa.^[30] Jedna druga PET studija je utvrdila negativnu korelaciju između stepena 5-HT_1A 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

• 5-CT
• 5-MeO-DMT
• 5-MT
• 8-OH-DPAT
• Adatanserin
• αET
• Alnespiron
• αMT
• Aripiprazol
• Asenapin
• Bay R 1531
• Befiradol
• Binospiron
• Bufotenin
• Buspiron
• Kanabidiol
• Klozapin
• Dihidroergotamin
• DMT
• Ebalzotan
• Eltoprazin
• Eptapiron
• Ergotamin
• Etoperidon
• F-11,461
• F-12,826
• F-13,714
• F-14,679
• F-15,599
• Flesinoksan
• Flibanserin
• Gepiron
• Ipsapiron
• Lesopitron
• Lisurid
• LSD
• Lu AA21004
• LY-293,284
• LY-301,317
• MDMA
• MKC-242
• NBUMP
• Nefazodon
• Osemozotan
• Perospiron
• Piklozotan
• Psilocin
• Psilocibin
• PRX-00023
• Rauvolscin
• Repinotan
• RU-24,969
• S-15,535
• Sarizotan
• SSR-181,507
• Sunepitron
• Tandospiron
• Tiospiron
• Trazodon
• U-92,016-A
• Urapidil
• Vilazodon
• Johimbin
• Ksaliproden
• Zalospiron
• Ziprasidon

Antagonisti

• Alprenolol
• AV-965
• BMY-7,378
• Cijanopindolol
• Dotarizin
• Flopropion
• GR-46,611
• Jodocijanopindolol
• Izamoltan
• Lekozotan
• Metiotepin
• MPPF
• NAN-190
• Oksprenolol
• Pindobind
• Pindolol
• Propranolol
• Robalzotan
• SB-649,915
• SDZ-216,525
• Spiperon
• Spiramid
• Spiroksatrin
• UH-301
• WAY-100,135
• WAY-100,635
• Ksilamidin

Genetika

5-HT_1A 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

Za 5-HT_1A 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]

Povezano

• 5-HT receptor
• 5-HT₁ receptor

Literatura

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Dodatna literatura

• 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. DOI:10.1007/BF00965820. PMID 2052135. 
• Hensler JG (2003). „Regulation of 5-HT1A receptor function in brain following agonist or antidepressant administration”. Life Sci. 72 (15): 1665–82. DOI:10.1016/S0024-3205(02)02482-7. PMID 12559389. 
• 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. DOI:10.1016/S0024-3205(03)00141-3. PMID 12650852. 
• 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 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. 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 332551. 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

• „5-HT_1A”. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Arhivirano iz originala na datum 2012-09-02. Pristupljeno 2014-05-01.