Wikipedia

HTR2A

Receptor 5-HT2A je podtip receptora5-HT2 porodice serotononskih G protein-spregnutih receptora (GPCR).[4] Recweptor 5-HT2A je receptor ćelijske površine.[5] 5-HT je skraćenica za 5-hidroksi-triptamin, koji je serotonin. Ovo je glavni podtip ekscitacijskog receptora među GPCR za serotonin, iako 5-HT2A također može imati inhibitorni učinak[6] na određenim područjima kao što su vizuelni i orbitofrontalni korteks.[7] Ovaj receptor je prvi put zapažen po svom značaju kao meta serotonergični psihodelični lijekovi kao što su LSD i psilocibinska gljiva. Kasnije se vratio na vidjelo jer je utvrđeno da je barem djelomično posredovao u djelovanju mnogih antipsihotičnih lijekova, posebno atipskih.

HTR2A
Identifikatori
AliasiHTR2A
Vanjski ID-jeviOMIM: 182135 MGI: 109521 HomoloGene: 68073 GeneCards: HTR2A
Lokacija gena (čovjek)
Hromosom 13 (čovjek)
Hrom.Hromosom 13 (čovjek)[1]
Hromosom 13 (čovjek)
Genomska lokacija za HTR2A
Genomska lokacija za HTR2A
Bend13q14.2Početak46,831,546 bp[1]
Kraj46,897,076 bp[1]
Obrazac RNK ekspresije


Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija• 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding
• G protein-coupled receptor activity
• virus receptor activity
• signal transducer activity
• G-protein alpha-subunit binding
• G protein-coupled serotonin receptor activity
• serotonin binding
• neurotransmitter receptor activity
• GO:0001948, GO:0016582 vezivanje za proteine
• GO:0032403 protein-containing complex binding
Ćelijska komponenta• citoplazma
• integral component of membrane
• citosol
• projekcija ćelije
• membrana
• cell body fiber
• integral component of plasma membrane
• dendritic shaft
• Akson
• soma
• Kaveole
• GO:0016023 citoplazmatska vezikula
• ćelijska membrana
• dendrit
• glutamatergic synapse
• integral component of postsynaptic membrane
• integral component of presynaptic membrane
Biološki proces• detection of mechanical stimulus involved in sensory perception of pain
• release of sequestered calcium ion into cytosol
• regulation of dopamine secretion
• phospholipase C-activating serotonin receptor signaling pathway
• urinary bladder smooth muscle contraction
• positive regulation of MAP kinase activity
• behavioral response to cocaine
• positive regulation of cytosolic calcium ion concentration
• positive regulation of kinase activity
• positive regulation of phosphatidylinositol biosynthetic process
• GO:0010260 starenje
• cellular calcium ion homeostasis
• Ćelijska smrt
• Memorija
• activation of phospholipase C activity
• detection of temperature stimulus involved in sensory perception of pain
• protein localization to cytoskeleton
• Spavanje
• positive regulation of vasoconstriction
• positive regulation of cell population proliferation
• negative regulation of potassium ion transport
• positive regulation of ERK1 and ERK2 cascade
• artery smooth muscle contraction
• positive regulation of peptidyl-tyrosine phosphorylation
• viral entry into host cell
• phosphatidylinositol 3-kinase signaling
• Nocicepcija
• temperature homeostasis
• GO:0022415 viral process
• positive regulation of fat cell differentiation
• positive regulation of glycolytic process
• negative regulation of synaptic transmission, glutamatergic
• GO:0072468 Transdukcija signala
• chemical synaptic transmission
• serotonin receptor signaling pathway
• phospholipase C-activating G protein-coupled receptor signaling pathway
• G protein-coupled receptor signaling pathway
• GO:0035737 životinjsko ponašanje
• regulation of synaptic vesicle exocytosis
• G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez

3356

15558

Ensembl

ENSG00000102468

ENSMUSG00000034997

UniProt

P28223

P35363

RefSeq (mRNK)

NM_001165947
NM_000621
NM_001378924

NM_172812

RefSeq (bjelančevina)

NP_000612
NP_001159419
NP_001365853

NP_766400

Lokacija (UCSC)Chr 13: 46.83 – 46.9 Mbn/a
PubMed pretraga[2][3]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Smanjena regulacija postsinapsnihih receptora 5-HT2A je adaptivni proces izazvan hroničnom primjenom selektivnih inhibitora preuzimanja serotonina (SSRI) i atipskih antipsihotika. Samoubilački i na drugi način depresivni pacijenti imali su više receptora 5-HT2A od normalnih pacijenata. Ovi nalazi ukazuju na to da je postsinapsna prekomjerna gustoća 5-HT2A uključena u patogenezu depresije.[8]

Paradoksalna podregulacija receptora 5-HT2A može se primijetiti s nekoliko antagonista 5-HT 2A.[9] Prema tome, umjesto tolerancije, od antagoniste 5-HT2A očekivala bi se reverzna tolerancija. Međutim, na ovom mjestu postoji barem jedan antagonist za koji je pokazano da poboljšava receptore 5-HT2A.[10] Osim toga, nekoliko drugih antagonista možda neće uticati na broj receptora 5-HT2A.[11] Ipak, nadregulacija je prije izuzetak nego pravilo. Niti tolerancija niti odskok ne primjećuju se kod ljudi s obzirom na SWS koji promovira efekte antagonista 5-HT2A.[12]

Aminokiselinska sekvenca

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Dužina polipeptidnog lanca je 471 aminokiselina, a molekulska težina 52.603 Da.[13]

1020304050
MDILCEENTSLSSTTNSLMQLNDDTRLYSNDFNSGEANTSDAFNWTVDSE
NRTNLSCEGCLSPSCLSLLHLQEKNWSALLTAVVIILTIAGNILVIMAVS
LEKKLQNATNYFLMSLAIADMLLGFLVMPVSMLTILYGYRWPLPSKLCAV
WIYLDVLFSTASIMHLCAISLDRYVAIQNPIHHSRFNSRTKAFLKIIAVW
TISVGISMPIPVFGLQDDSKVFKEGSCLLADDNFVLIGSFVSFFIPLTIM
VITYFLTIKSLQKEATLCVSDLGTRAKLASFSFLPQSSLSSEKLFQRSIH
REPGSYTGRRTMQSISNEQKACKVLGIVFFLFVVMWCPFFITNIMAVICK
ESCNEDVIGALLNVFVWIGYLSSAVNPLVYTLFNKTYRSAFSRYIQCQYK
ENKKPLQLILVNTIPALAYKSSQLQMGQKKNSKQDAKTTDNDCSMVALGK
QHSEEASKDNSDGVNEKVSCV
Simboli

C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin

Distribucija

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5-HT2A je široko eksprimiran u centralnom nervnom sistemu (CNS). Ispolava se u blizini većine područja bogatih serotonergijskim terminalima, uključujući neokorteks (uglavnom prefrontalni, parietalni i somatosenzorni korteks) i olfaktorni tuberkulom. Posebno visoke koncentracije ovog receptora na apikalni dendritima piramidnih ćelija u sloju V korteksa mogu modulirati kognitivne procese, radnu memoriju i pažnju[14][15][16] pojačavanjem oslobađanja glutamata, nakon čega slijedi složen raspon interakcija s 5-HT1A,[17] GABAA,[18] adenozin A1,[19] AMPA,[20] mGluR2/3,[21] mGlu5,[22] i receptori OX2.[23][24] U malom mozgu pacova, protein je takođe pronađen u Golgijevim ćelijama zrnastog sloja,[25] i u Purkinjeovim ćelijama.[26][27]

Na periferiji je visoko eksprimiran u trombocitima i mnogim tipovima ćelija kardiovaskularnog sistema, u fibroblastima i u neuronima perifernog nervnog sistema. Osim toga, ekspresija iRNK za 5-HT2A primijećena je kod ljudskih monocita.[28] Distribucija agonista receptora 5-HT2A/2C u cijelom tijelu, [11C] Cimbi-36 pokazuje unos u nekoliko unutrašnjih organa i smeđe masno tkivo (BAT), ali nije jasno predstavlja li to specifično vezivanje za receptore 5-HT2A.[29]

Signalna kaskada

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Poznato je da se receptor 5-HT2A prvenstveno spaja sa Gαq putem transdukcije signala. Nakon stimulacije receptora preko agonista, Gαq i β-γ podjedinice disociraju kako bi pokrenuli nizvodne efektorske putove. Gα q stimulira aktivnost fosfolipaza C (PLC), što kasnije podstiče oslobađanje diacilglicerola (DAG) i inozitol-trifosfata (IP3), koji zauzvrat stimuliraju aktivnost protein-kinaza C (PKC) i oslobađanje Ca2+.[30]

Efekti

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Fiziološki procesi posredovani receptorom uključuju:

Genetika

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Hromosom 13.

Receptori 5-HT2A kodirani su genom HTR2A . Kod ljudi gen se nalazi na hromozomu 13. Gen se ranije zvao samo HTR2 do opisa dva povezana gena HTR2B i HTR2C. Za HTR2A je identificirano nekoliko zanimljivih polimorfizama): A-1438G (rs6311), C102T (rs6313) i His452Tyr (rs6314). Za ovaj gen postoji mnogo više vezanih polimorfizama. U dokumentu iz 2006. godine navedeno ih je 255.[42]

Vjerojatna uloga u fibromialgiji kao polimorfizmi T102C gena 5HT2A bili su česti u pacijenata s fibromialgijom.[43]

Smatra se da se ljudskii gen HTR2A sastoji od tri introna i četiri egzona i da se preklapa s ljudskim genom HTR2A-AS1 ,koji se sastoji od 18 egzona.[44] Postoji više od 200 organizama koji imaju orthologa s ljudskim HTR2A. Najbolje dokumentirani ortolozi za gen HTR2Asu mišji[45] i zebricin.[46] Postoji osam paraloga za gen HTR2A. Poznato je da gen HTR2A stupa u interakciju i aktivira gene za G-proteine kao što su GNA14, GNAI1, GNAI3, GNAQ, i GNAZ.[47] Ove interakcije su kritične za ćelijsku signalizaciju [48][49] i homeostazu [50] imnogih organizama.[51]

U ljudskom moždanom tkivu regulacija HTR2A varira ovisno o regiji: frontalni korteks, amigdala, talamus, moždano stablo i mali mozak. U radu iz 2016. otkrili su da HTR2A prolazi kroz različite prerade, uključujući i alternativnua akceptorska mjesta, preskakanje egzona , rijetku upotrebu egzona i zadržavanje introna.

Mehanizmi regulacije

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Postoji nekoliko mehanizama regulacije za gen HTR2A koji je reguliran metilacijom DNK na određenim mjestima vezanja za transkript.[52][53] Ostali mehanizmi za ispravnu regulaciju ekspresije gena postižu se alternativnom preradom. Ovo je kotranskripcijski proces, koji omogućuje generiranje više oblika transkripta iRNK iz jedne kodirajuće jedinice i pojavljuje se kao važna kontrolna tačka za ekspresiju gena. U ovom procesu, egzoni ili introni mogu biti uključeni ili isključeni iz prekursorne-iRNK, što rezultira u više zrelih varijanti iRNK.[54] Ove varijante iRNK rezultiraju različitim izoformama koje mogu imati antagonističke funkcije ili različite obrasce ekspresije, dajući ćelijama plastičnost i prilagodljivost.[55] One study found that the common genetic variant rs6311 regulates expression of HTR2A transcripts containing the extended 5’ UTR.

Jedno istraživanje otkrilo je da uobičajena genetička varijanta rs6311 regulira ekspresiju transkripata HTR2A koji sadrže prošireni 5' UTR.

Pridruženi psihijatrijski poremećaji

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Nekoliko studija je pokazalo veze između polimorfizma -1438G/A i poremećaja raspoloženja, kao što je bipolarni poremećaj[56] i glavni depresivni poremećaj.[57]

Između polimorfizma T102C i shizofrenije pronađena je slaba veza s omjerom vjerovatnoće od 1,3.[58]

Ovaj polimorfizam je također proučavan u odnosu na pokušaje samoubistva, pri čemu je studija među pokušajima samoubistva otkrila višak genotipova C/C.[59]

Ove pojedinačne studije, međutim, možda ne daju potpunu sliku: pregled iz 2007. koji se bavi učinkom različitih jednonukleotidnih polimorfizama objavljen u odvojenim studijama navodi da su "studije genetičke povezanosti" varijanti gena "HTR2A" s psihijatrijskim poremećajima ] pr kontradiktorne i općenito sa negativnim rezultatima "bez učešća, male ili neopisane uloge genetičke varijante gena".[60]

Polimorfizmi u promotorskom genu, koji kodira rani odgovor na rast 3 (EGR3) povezani su sa shizofrenijom. Studije su pokazale vezu između EGR3 i HTR2A i ponašanja sličnog shizofreniji kod transgenih životinja.[61][62] Exactly how these results translate over to further biopsychological understanding of schizophrenia is still widely debated.[63][64] Postoje neki dokazi da disfunkcija "HTR2A" može uticati na farmakološke intervencije.[65]

Odgovor na liječenje

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Čini se da je i genetikčka osnova donekle povezana s količinom nuspojava u liječenju velikog depresivnog poremećaja.[66]

Veze sa zloupotrebom supstanci

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Pokazalo se da polimorfizmi receptora 5-HT2A kodirajućem genu HTR2A (rs6313 i s6311) imaju sukobljeneveze sa zloupotrebom alkohola. Naprimjer, prijavljeno je da polimorfizam gena za kodiranje 5-HT2A receptora HTR2A (rs6313) predviđa niže pozitivno očekivano trajanje alkohola u krvi, veću odbijajuću samoefikasnost i manju zloupotrebu alkohola u uzorku od 120 mladih odraslih osoba. Međutim, ovaj polimorfizam nije ublažio veze između impulzivnosti, spoznaje i zloupotrebe alkohola [67] Postoje i oprečni rezultati jer su druge studije otkrile povezanost polimorfizama T102C sa zloupotrebom alkohola.[68][69]

Uticaj lijekova na ekspresiju gena

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Postoje neki dokazi da obrasci metilacije mogu doprinijeti relapsu ponašanja kod ljudi koji koriste stimulanse.[70] Kod miševa, psihotropni lijekovi kao što su DOI, LSD, DOM i DOB proizveli su različite obrasce transkripcije među nekoliko različitih regija mozga.

Reference

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