Wikipedia

Androgeni receptor

Androgeni receptor (AR), poznat i kao NR3C4 (potporodica jedarnih receptora 3, grupa C, član 4), je tip jedarnih receptora[5] koji se aktivira vezanjem bilo kog od androgenih hormona, uključujući testosteron i dihidrotestosteron[6] u citoplazmi, a zatim se translocira u jedro. Receptor androgena je u najbližoj vezi sa progesteronskim receptorom, a progestin u većim dozama može blokirati androgeni receptor.[7][8]

Androgeni receptor
Identifikatori
SimbolAR
Alt. simboliAR, AIS, AR8, DHTR, HUMARA, HYSP1, KD, NR3C4, SBMA, SMAX1, TFM, androgen receptor
Raspon tkivne ekspresije gena AC
OMIM313700
Ortolozi28
UniProt[https://www.uniprot.org/uniprot/P10275

Q9NUA2 P10275

Q9NUA2]
Ostali podaci
LokusHrom. X [https://omim.org/search/?index=geneMap&search=Xq

Band =Xq12{{{bend}}} q

Band =Xq12{{{bend}}}{{{lokus_dopunski_podaci}}}]
Pretraga za
Strukture[https://swissmodel.expasy.org/repository/uniprot/P10275
Q9NUA2 Swiss-model]
Domene[https://www.ebi.ac.uk/interpro/protein/P10275
Q9NUA2 InterPro]
Kod čovjeka, gen AR nalazi se na dugom (q) kraku X-hromosoma, pozicija Xq12
Androgeni receptor
Kristalna struktura domena vezanja liganda ljudskog androgenih receptora vezana za nh2-terminalni peptid androgenih receptora ar20-30 i r1881
Identifikatori
SimbolAR
Normalna funkcija androgenog receptora.
Testosteron (T) ulazi u ćeliju i, ako je prisutna 5-alfa-reduktaza, pretvara se u dihidrotestosteron (DHT).
Nakon vezanja steroida, androgeni receptor (AR) prolazi kroz konformacijsku promjenu i oslobađa proteine toplotnog šoka (hsps).
Fosforilacija (P) se javlja prije ili poslije vezanja steroida.
AR se translocira u jedro, gdje dolazi do dimerizacije, vezivanja DNK i regrutacije koaktivatora.
Ciljni geni se transkribiraju (mRNA) i prevode u proteine.[1][2][3][4]

Glavna funkcija receptora androgena je vezanje DNK faktora transkripcije koji regulira ekspresiju gena;[9] međutim, androgeni receptor ima i druge funkcije.[10] Geni regulirani androgenom kritični su za razvoj i održavanje muškog spolnog fenotipa.

Funkcija

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Efekti na razvoj

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U nekim tipovima ćelija, testosteron direktno komunicira sa androgenim receptorima, dok ga u drugim 5-alfa reduktaza pretvara u dihidrotestosteron, još snažniji agonist za aktivaciju androgenih receptora.[11] Testosteron se javlja kao primarni hormon koji aktivira androgene receptore u Wolffovom kanalu, dok je dihidrotestosteron glavni androgeni hormon u urogenitalnom sinusu, urogenitalnom tuberkulumu i dlakinim folikulima.[12] Testosteron je stoga odgovoran prvenstveno za razvoj muških primarnih spolnih obilježja, dok je dihidrotestosteron odgovoran za sekundarne muške spolne karakteristike.

Androgeni uzrokuju sporo sazrijevanje kostiju, ali veći učinak snažnog sazrijevanja dolazi od estrogena proizvedenog aromatizacijom androgena. Korisnici steroida u tinejdžerskoj dobi mogu otkriti da je njihov rast zaustavio višak androgena i / ili estrogena. Ljudi s premalo spolnih hormona mogu biti niski tokom puberteta, ali na kraju su viši od prosjeka odraslih kao u sindromu neosjetljivosti na androgen ili sindromu neosjetljivosti na estrogen.[13]

Studije nokaut-miševa pokazale su da je androgeni receptor neophodan za normalnu plodnost žena, potreban za razvoj i punu funkcionalnost folikula jajnika i ovulacije, djelujući preko oba jajnika i neuroendokrinim mehanizmima.[14]

Održavanje integriteta muškog skeleta

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Preko androgenih receptora, androgeni imaju ključnu ulogu u održavanju integriteta muškog skeleta. Regulacija ovog integriteta signalizacijom androgenih receptora (AR) može se pripisati i osteoblastima i osteocitima.[15]

Uloga kod žena

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AR ima ulogu u regulaciji ženskih seksualnih, somatskih etoloških funkcija. Eksperimentalni podaci korištenjem AR knokout ženskih miševa pružaju dokaze da je promocija srčanog rasta, hipertrofije bubrega, rasta kortikalne kosti i regulacije trabekulske koštane strukture rezultat djelovanja ovisnih o DNK AR-a kod žena.

Štaviše, važnost razumijevanja ženskih androgenih receptora leži u njihovoj ulozi u nekoliko genetički kontroliranih poremećaja, uključujući sindrom neosjetljivosti na androgene (AIS). kompletni (CAIS) i djelimični (PAIS) koji su rezultat mutacije u genima koji kodiraju AR. Ove mutacije uzrokuju inaktivaciju AR-a, zbog mutacija koje daju otpor cirkulirajućem testosteronu, a prijavljeno je više od 400 različitih mutacija AR-a.

Mehanizam djelovanja

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Genomski

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Primarni mehanizam djelovanja za androgene receptore je direktna regulacija transkripcije gena. Vezanje androgena za androgeni receptor rezultira konformacijskom promjenom u receptoru, što zauzvrat uzrokuje disocijaciju proteina toplotnog šoka, transporta iz citosola u ćelijska jedra i dimerizaciju. Dimer androgenih receptora veže se za određenu sekvencu DNK poznatu kao element hormonskog odgovora. Androgeni receptori komuniciraju s drugim proteinima u jedru, što rezultira regulacijom prema gore ili dolje specifične transkripcije gena.[16] Povećana regulacija ili aktivacija transkripcije rezultira povećanom sintezom iRNK, koju prevode ribosomi da bi se proizveli specifični proteini. Jedan od poznatih ciljnih gena aktivacije androgenih receptora je insulinoliki receptor faktora rasta (IGF-1R).[17] Stoga su promjene nivoa specifičnih proteina u ćelijama jedan od načina na koji androgeni receptori kontroliraju ponašanje ćelija.

Jedna funkcija androgenih receptora koja je neovisna od direktnog vezanja za njegovu ciljnu sekvencu DNK olakšava se regrutacijom putem drugih DNK-vržućih proteina. Jedan od primjera je faktor odgovora u serumu, protein koji aktivira nekoliko gena koji uzrokuju rast mišića.[18]

Androgeni receptor se modificira u post-translacijskoj modifikaciji putem acetilacije,[19] koja direktno promovira transaktivaciju, apoptozu posredovanu AR-om[20] i rast ćelija kontaktno-neovisnog karcinoma prostate.[21] Acetilacija AR-a inducuranu pomoću androgena[22] određuje regrutaciju u hromatinu.[23] Mjesto acetilacije AR-a ključna je meta NAD-zavisne i TSA-zavisne histonske deacetilaze i duge nekodirajuće RNK.[24]

Negenomski

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Dedavno pokazalo se da androgeni receptori imaju drugi način djelovanja. Kao što je utvrđeno i za druge receptore steroidnih hormona, kao što su estrogeni receptori, androgeni receptori mogu djelovati neovisno o njihovoj interakciji s DNK.[25] Androgeni receptori stupaju u interakciju sa određenim proteinima prenošenja signala u citoplazmi. Vezanje androgena na citoplazmatske androgene receptore može prouzrokovati brze promjene u funkciji ćelija, neovisno o promjenama u transkripciji gena, poput promjena u transportu iona. Regulacija puteva transdukcije signala citoplazmatskim androgenim receptorima može indirektno dovesti do promena u transkripciji gena, naprimjer, dovodeći do fosforilacije drugih faktora transkripcije.

Genetika

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Gen

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Kod ljudi, androgeni receptor je kodiran AR genom koji se nalazi na X hromosomu na poziciji Xq11-12.[26][27]

Nedostaci

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Sindrom neosjetljivosti na androgen, prije poznat kao feminizacija testisa, uzrokovan je mutacijom gena androgenih receptora na X hromosomu (lokus: Xq11 – Xq12). Čini se da androgeni receptor utiče na neuronsku fiziologiju i oštećen je Kenneddyjevom bolešču.[28] Androgeni receptor utiče na fiziologiju neurona i oštećuje ga Kennedyjeva bolest.[29][30] Pored toga, tačkaste mutacije i polimorfizam trinukleotidno ponavljanje povezani su s nizom dodatnih poremećaja.[31]

Ponavljanja C-A-G

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AR gen sadrži ponavljanja sekvence C-A-G koja utiču na funkciju receptora, gdje manje ponavljanja dovodi do povećane osjetljivosti receptora na cirkulirajuće androgene, a više ponavljanja dovodi do smanjene osjetljivosti receptora. Studije su pokazale da postoje rasne varijacije u ponavljanjima CAG,[32][33] s tim da Afroamerikanci imaju manje ponavljanja od kavkazoidnih Amerikanaca koji nisu Latinoamerikanci.[32] Rasni trendovi u CAG ponavljanuju imaju paralelu sa incidencijom i smrtnošću od raka prostate u ovim skupinama.

Struktura

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Strukturni domeni dvije izoforme (AR-A i AR-B) ljudskih androgenih receptora.
Brojevi iznad traka odnose se na aminokiselinske ostatke koji razdvajaju domene, počevši od N-kraja (lijevo) do C-kraja (desno).
NTD = N-terminalni domen, DBD = DNA-vezujući domen, LBD = ligand-vezujući domen, AF = funkcija aktivacije.

Izoforme

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Identificirane su dvije izoforme receptora androgena (A i B):[34]

Domeni

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Poput ostalih jwedarnih receptora, androgeni receptor je modularne strukture i sastoji se od sljedećih funkcionalnih domena označenih sa A do F:[36]

Također pogledajte

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Reference

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