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OPRM1

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OPRM1
Identifikatori
AliasiOPRM1
Vanjski ID-jeviOMIM: 600018 MGI: 97441 HomoloGene: 37368 GeneCards: OPRM1
Lokacija gena (čovjek)
Hromosom 6 (čovjek)
Hrom.Hromosom 6 (čovjek)[1]
Hromosom 6 (čovjek)
Genomska lokacija za OPRM1
Genomska lokacija za OPRM1
Bend6q25.2Početak154,010,496 bp[1]
Kraj154,246,867 bp[1]
Lokacija gena (miš)
Hromosom 10 (miš)
Hrom.Hromosom 10 (miš)[2]
Hromosom 10 (miš)
Genomska lokacija za OPRM1
Genomska lokacija za OPRM1
Bend10 A1|10 1.85 cMPočetak6,708,506 bp[2]
Kraj6,988,198 bp[2]
Obrazac RNK ekspresije
Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija voltage-gated calcium channel activity
morphine receptor activity
G protein-coupled receptor activity
neuropeptide binding
signal transducer activity
filamin binding
G protein-coupled opioid receptor activity
GO:0001948, GO:0016582 vezivanje za proteine
beta-endorphin receptor activity
G-protein alpha-subunit binding
protein C-terminus binding
protein domain specific binding
G-protein beta-subunit binding
peptide binding
Ćelijska komponenta postsynapse
citoplazma
integral component of membrane
perikaryon
Golđijev aparat
membrana
focal adhesion
integral component of plasma membrane
dendrite membrane
Endoplazmatski retikulum
neuron projection
Lipidni splav
Sarkolema
dendrite cytoplasm
ćelijska membrana
dendrit
endozom
Akson
projekcija ćelije
spine apparatus
integral component of postsynaptic membrane
integral component of presynaptic membrane
Biološki proces positive regulation of appetite
negative regulation of adenylate cyclase activity
adenylate cyclase-activating dopamine receptor signaling pathway
sensory perception
negative regulation of cAMP-mediated signaling
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway
regulation of sensory perception of pain
eating behavior
locomotory behavior
estrous cycle
positive regulation of cytosolic calcium ion concentration
positive regulation of nitric oxide biosynthetic process
G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger
negative regulation of Wnt protein secretion
Zarastanje rana
acute inflammatory response to antigenic stimulus
positive regulation of cAMP-mediated signaling
positive regulation of neurogenesis
regulation of NMDA receptor activity
phospholipase C-activating G protein-coupled receptor signaling pathway
response to morphine
response to lipopolysaccharide
negative regulation of nitric oxide biosynthetic process
calcium ion transmembrane transport
excitatory postsynaptic potential
positive regulation of ERK1 and ERK2 cascade
behavioral response to ethanol
response to food
Nocicepcija
response to radiation
response to growth factor
response to ethanol
GO:0072468 Transdukcija signala
negative regulation of cell population proliferation
negative regulation of cytosolic calcium ion concentration
adenylate cyclase-inhibiting opioid receptor signaling pathway
response to cocaine
cellular response to morphine
chemical synaptic transmission
neuropeptide signaling pathway
G protein-coupled opioid receptor signaling pathway
G protein-coupled receptor signaling pathway
cytokine-mediated signaling pathway
GO:1904490 regulation of cellular response to stress
negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway
adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)
NM_000914
NM_001008503
NM_001008504
NM_001008505
NM_001145279

NM_001145280
NM_001145281
NM_001145282
NM_001145283
NM_001145284
NM_001145285
NM_001145286
NM_001145287
NM_001285522
NM_001285523
NM_001285524
NM_001285526
NM_001285527
NM_001285528

NM_001039652
NM_011013
NM_001302793
NM_001302794
NM_001302795

NM_001302796
NM_001304937
NM_001304938
NM_001304948
NM_001304950
NM_001304955

RefSeq (bjelančevina)
NP_000905
NP_001008503
NP_001008504
NP_001008505
NP_001138751

NP_001138752
NP_001138753
NP_001138754
NP_001138755
NP_001138756
NP_001138757
NP_001138758
NP_001138759
NP_001272451
NP_001272452
NP_001272453
NP_001272455
NP_001272456
NP_001272457

NP_001034741
NP_001289722
NP_001289723
NP_001289724
NP_001289725

NP_001291866
NP_001291867
NP_001291877
NP_001291879
NP_001291884

Lokacija (UCSC)Chr 6: 154.01 – 154.25 MbChr 10: 6.71 – 6.99 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš
Aktivi i neaktivni μ-opioidni receptori[5]

μ-Opioidni receptori (MOR) jesu protein koji je kod ljudi kodiran genom MOR. To je klasa opioidnih receptora sa visokim afinitetom za encefaline i beta-endorfine, ali niskim afinitetom za dinorfine. Također se nazivaju μ (mu)-opioidni peptidni (MOP) receptori. Prototipni μ-opioidni receptorski agonist je morfij, primarni psihoaktivni alkaloid u opijumu. To je inhibitorni receptor vezan za G-protein koji aktivira podjedinicu Gi alfa, inhibirajući aktivnost adenilat-ciklaza, snižavajući cAMP.

Aminokiselinska sekvenca

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Dužina polipeptidnog lanca je 400 aminokiselina, а molekulska težina Da. 44 779[6]

1020304050
MDSSAAPTNASNCTDALAYSSCSPAPSPGSWVNLSHLDGNLSDPCGPNRT
DLGGRDSLCPPTGSPSMITAITIMALYSIVCVVGLFGNFLVMYVIVRYTK
MKTATNIYIFNLALADALATSTLPFQSVNYLMGTWPFGTILCKIVISIDY
YNMFTSIFTLCTMSVDRYIAVCHPVKALDFRTPRNAKIINVCNWILSSAI
GLPVMFMATTKYRQGSIDCTLTFSHPTWYWENLLKICVFIFAFIMPVLII
TVCYGLMILRLKSVRMLSGSKEKDRNLRRITRMVLVVVAVFIVCWTPIHI
YVIIKALVTIPETTFQTVSWHFCIALGYTNSCLNPVLYAFLDENFKRCFR
EFCIPTSSNIEQQNSTRIRQNTRDHPSTANTVDRTNHQLENLEAETAPLP

Struktura

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Krioelektronska mikroskopska struktura kompleksa μ-opioidnih receptora – Gi proteina objavljena je u 2018.[7]

Dobro su okarakterizirane tri varijante μ-opioidnog receptora, iako je lančana reakcija polimeraze reverzne transkripcije u realnom vremenu identificirala do 10 ukupnih varijanti prerade kod ljudi.[8][9][10]

μ1 1 opioidnom receptoru zna se više nego o ostalim varijantama.
μ2 TRIMU 5 je selektivni agonist receptora μ2.[11]
μ3 Varijanta μ3 prvi puta opisana je 2003.[12] Reagira na opijatne alkaloide, ali ne i opioidne peptide.[13]

Lokacija

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Mogu postojati presinapsni ili postsinapsni, ovisno o tipu ćelije.

Μ-opioidni receptori uglavnom postoje kao presinapsni saveznici u periakvaduktnoj sivoj regiji i u površinskom leđnom rogu kičmene moždine (posebno Rolandovoj substantia gelatinosa). Ostala područja na kojima su se nalazili uključuju vanjski pleksiformni sloj mirisnog režnje, nucleus accumbens, u nekoliko slojeva moždane kore i u nekim od amigdalnom jezgru, kao i jezgru usamljenog trakta.

Neki MOR također nalaze se u crijevnom traktu. Aktivacija ovih receptora inhibira djelovanje peristaltike, što koje uzrokuje zatvor, glavnu nuspojavu μ agonista.[14]

Aktivacija

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MOR može posredovati u akutnim promjenama neuronske ekscitabilnosti, suzbijanjem presinapsnog oslobađanja GABA. Aktivacija MOR-a dovodi do različitih učinaka na dendritske bodlje, ovisno o agonistima, a može biti primjer funkcionalne selektivnosti na μ-receptoru.[15] Ostaje da se razjasne fiziološke i patološke uloge ova dva različita mehanizma. Možda bi oba mogla biti uključeni u ovisnost o opioidima i opioidom izazvane deficite u spoznaji.

Aktivacija μ-opioidnog receptora putem agonista kao što je morfij uzrokuje analgeziju, sedaciju, blago snižen krvni pritisak, svrbež, mučninu , euforiju, smanjeno disanje, miozu (sužene zjenica) i smanjenu pokretljivost crijeva koja često dovodi do konstipacija. Neki od ovih učinaka, poput analgezije, sedacije, euforije, svrbeža i smanjenog disanja, imaju tendenciju da se smanjuju uz nastavak upotrebe, kako se razvija tolerancija. Mioza i smanjena peristaltika crijeva nastoje opstati; na ove efekte razvija se mala tolerancija.

Kanonska izoforma MOR1 odgovorna je za analgeziju izazvanu morfijem, dok je alternativno prerađena izoforma MOR1D (putem heterodimerizacije sa peptidnim receptorom koji oslobađa gastrin) potrebna za svrab izazvan morfijom.[16]

Deaktivacija

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Kao i kod drugih G-protein spregnutih receptora, signalizacija pomoću μ-opioidnog receptora prekida se putem nekoliko različitih mehanizama, koji su pojačano regulirani hroničnom upotrebom, što dovodi do brze tahifilaksije.[17] Najvažniji regulatorni proteini za MOR su β-arestin ареstin beta 1 i arestin beta 2,[18][19][20] i proteini RGS RGS4, RGS9-2, RGS14 i RGSZ2.[21][22]

Dugotrajna ili visoka doza opioida također može dovesti do uključivanja dodatnih mehanizama tolerancije. To uključuje smanjenu ekspresiju gena MOR, pa se broj receptora prisutnih na površini ćelije zapravo smanjuje, za razliku od kratkotrajne desenzibilizacije izazvane β-arestinima ili RGS proteinima.[23][24][25] Druga dugotrajna prilagodba na upotrebu opijata može biti pojačana regulacija glutamatnih i drugih puteva u mozgu koji mogu imati opioidno suprotan učinak, pa smanjuje učinke opioidnih lijekova, mijenjanjem nizvodnih puteva, bez obzira na aktivaciju MOR-a.[26][27]

Tolerancija i predoziranja

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Smrtonosno predoziranje opioidima obično se javlja zbog bradipnea, hipoksemija i smanjenja srčanog volumena (hipotenzija se javlja zbog vazodilatacija, i bradikardija dodatno doprinoseči smanjenju minutnog volumena srca).[28][29][30] Učinak potenciranja javlja se kada se opioidi kombiniraju s etanolom, benzodiazepinom ili barbituratima, što rezultira povećanim rizikom od predoziranja.[28][29] Znatna tolerancija na respiratornu depresiju brzo se razvija i tolerantne osobe mogu izdržati veće doze.[31] Međutim, tolerancija na respiratornu depresiju gubi se jednako brzo tokom odvikavanja.[31] Mnoga predoziranja javljaju se kod ljudi koji zloupotrebljavaju svoje lijekove nakon što su dovoljno dugo bili u prekidu izgubli toleranciju na respiratornu depresiju. Manje često je poznato da masovna predoziranja uzrokuju cirkulatorni kolaps.

Predoziranje opioidima može se brzo poništiti upotrebom opioidnih antagonista, a nalokson je najrašireniji primjer.[28] Međutim, samo to obično nije dovoljno i obično je potrebna skrb podrške, kako bi se spriječile hipoksijske ozljede mozga praćenjem vitalnih znakova. Mogu biti potrebne i dodatne doze naloksona.

Takođerpogledajte

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Reference

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000112038 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000766 - Ensembl, maj 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Zhorov BS, Ananthanarayanan VS (mart 2000). "Homology models of mu-opioid receptor with organic and inorganic cations at conserved aspartates in the second and third transmembrane domains". Arch. Biochem. Biophys. 375 (1): 31–49. doi:10.1006/abbi.1999.1529. PMID 10683246.
  6. ^ "UniProt, P35372" (jezik: engleski). Pristupljeno 9. 10. 2021.
  7. ^ Koehl A, Hu H, Maeda S, et al. (2018). "Structure of the μ-opioid receptor-Gi protein complex". Nature. 558 (7711): 547–552. Bibcode:2018Natur.558..547K. doi:10.1038/s41586-018-0219-7. PMC 6317904. PMID 29899455.
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  15. ^ Liao D, Lin H, Law PY, Loh HH (februar 2005). "Mu-opioid receptors modulate the stability of dendritic spines". Proc. Natl. Acad. Sci. U.S.A. 102 (5): 1725–30. Bibcode:2005PNAS..102.1725L. doi:10.1073/pnas.0406797102. JSTOR 3374498. PMC 545084. PMID 15659552.
  16. ^ Liu XY, Liu ZC, Sun YG, Ross M, Kim S, Tsai FF, Li QF, Jeffry J, Kim JY, Loh HH, Chen ZF (2011). "Unidirectional Cross-Activation of GRPR by MOR1D Uncouples Itch and Analgesia Induced by Opioids". Cell. 147 (2): 447–458. doi:10.1016/j.cell.2011.08.043. PMC 3197217. PMID 22000021. SažetakWashington University in St. Louis Press Release.
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  24. ^ Lopez-Gimenez JF, Vilaró MT, Milligan G (novembar 2008). "Morphine desensitization, internalization, and down-regulation of the mu opioid receptor is facilitated by serotonin 5-hydroxytryptamine2A receptor coactivation". Molecular Pharmacology. 74 (5): 1278–91. doi:10.1124/mol.108.048272. PMID 18703670. S2CID 6310244.
  25. ^ Kraus J (2009). "Regulation of mu-opioid receptors by cytokines". Frontiers in Bioscience. 1: 164–70. doi:10.2741/e16. PMID 19482692.
  26. ^ García-Fuster MJ, Ramos-Miguel A, Rivero G, La Harpe R, Meana JJ, García-Sevilla JA (novembar 2008). "Regulation of the extrinsic and intrinsic apoptotic pathways in the prefrontal cortex of short- and long-term human opiate abusers". Neuroscience. 157 (1): 105–19. doi:10.1016/j.neuroscience.2008.09.002. PMID 18834930. S2CID 9022097.
  27. ^ Ueda H, Ueda M (2009). "Mechanisms underlying morphine analgesic tolerance and dependence". Frontiers in Bioscience. 14: 5260–72. doi:10.2741/3596. PMID 19482614.
  28. ^ a b c Blok (2017). "Opioid toxicity" (PDF). Clinical Key. Elsevier.
  29. ^ a b Hughes CG, McGrane S, Pandharipande PP (2012). "Sedation in the intensive care setting". Clinical Pharmacology. 4 (53): 53–63. doi:10.2147/CPAA.S26582. PMC 3508653. PMID 23204873.
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  31. ^ a b Zhilenko VN, Khoroshilova NV, Efremova VM (decembar 1989). "[Hygienic evaluation of atactic polypropylene]". Gigiena I Sanitariia. 10 (12): 86–7. PMID 2628209.

Vanjski linkovi

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Šablon:Neuropeptidni receptori Šablon:Opioidergici