CNR1

CNR1
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	1LVQ, 1LVR, 2B0Y, 2KOE, 2MZ3, 2MZ2, 2MZA,%%s1LVQ, 1LVR, 2B0Y, 2KOE
Identifikatori
Aliasi	CNR1
Vanjski ID-jevi	OMIM: 114610 MGI: 104615 HomoloGene: 7273 GeneCards: CNR1
Lokacija gena (čovjek)
Hrom.	Hromosom 6 (čovjek)
Kraj	88,166,347 bp
Lokacija gena (miš)
Hrom.	Hromosom 4 (miš)
Kraj	33,948,831 bp
Obrazac RNK ekspresije
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• G protein-coupled receptor activity; • signal transducer activity; • cannabinoid receptor activity; • GO:0001948, GO:0016582 vezivanje za proteine; • voltage-gated calcium channel activity involved in positive regulation of presynaptic cytosolic calcium levels;
Ćelijska komponenta	• integral component of membrane; • intracellular membrane-bounded organelle; • membrana; • growth cone; • integral component of plasma membrane; • Akson; • Lipidni splav; • ćelijska membrana; • presynaptic membrane; • mitohondrija; • mitochondrial outer membrane; • projekcija ćelije; • integral component of mitochondrial membrane; • presynapse; • glutamatergic synapse; • GABA-ergic synapse; • integral component of presynaptic membrane;
Biološki proces	• negative regulation of nitric-oxide synthase activity; • negative regulation of mast cell activation; • glucose homeostasis; • response to nutrient; • regulation of insulin secretion; • negative regulation of blood pressure; • adenylate cyclase-modulating G protein-coupled receptor signaling pathway; • maternal process involved in female pregnancy; • G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger; • response to nicotine; • GO:0010260 starenje; • positive regulation of fever generation; • Memorija; • negative regulation of action potential; • regulation of feeding behavior; • negative regulation of ion transport; • response to morphine; • negative regulation of fatty acid beta-oxidation; • response to lipopolysaccharide; • positive regulation of blood pressure; • regulation of penile erection; • regulation of lipid metabolic process; • Spermatogeneza; • positive regulation of neuron projection development; • positive regulation of apoptotic process; • positive regulation of acute inflammatory response to antigenic stimulus; • learning or memory; • Nocicepcija; • negative regulation of dopamine secretion; • regulation of synaptic transmission, glutamatergic; • response to ethanol; • axonal fasciculation; • regulation of synaptic transmission, GABAergic; • GO:0072468 Transdukcija signala; • response to cocaine; • trans-synaptic signaling by endocannabinoid, modulating synaptic transmission; • G protein-coupled receptor signaling pathway; • cannabinoid signaling pathway; • retrograde trans-synaptic signaling by endocannabinoid; • positive regulation of presynaptic cytosolic calcium concentration; • induction of synaptic vesicle exocytosis by positive regulation of presynaptic cytosolic calcium ion concentration;
	Izvori:Amigo / QuickGO
Ortolozi
	1268
	12801
	ENSG00000118432
	ENSMUSG00000044288
	P21554
	P47746
NM_001160226; NM_001160258; NM_001160259; NM_001160260; NM_016083;
	NM_033181; NM_001365869; NM_001365870; NM_001365872; NM_001365874; NM_001370545; NM_001370546; NM_001370547
	NM_007726; NM_001355020; NM_001355021; NM_001365881
NP_001153698; NP_001153730; NP_001153731; NP_057167; NP_149421;
	NP_001352798; NP_001352799; NP_001352801; NP_001352803; NP_001357474; NP_001357475; NP_001357476
	NP_031752; NP_001341949; NP_001341950; NP_001352810
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Kanabinoidni receptor tipa 1 (CB₁), znan i kao kanabinoid receptor 1, jest G protein-spregnuti kanabinoidni receptor koji je kod ljudi kodiran genom CNR1.^[5] Ljudski CB₁ receptor je eksprimiran u perifernom i centralnom nervnom sistemu. Aktivira se pomoću: endokanabinoida, grupe retrogradnih neurotransmitera koji uključuju anandamid i 2-arahidonoilglicerol (2-AG), biljni fitokanabinoid, kao što je spoj THC, koji je aktivni sastojak psihoaktivne droge kanabisa i, sintetski analozi THC-a. CB1 je antagoniziran pomoću fitokanabinoida tetrahidrokanabivarina (THCV).^[6]^[7]

Primarni endogeni agonist ljudskog receptora CB₁ je anandamid.^[5]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 472 aminokiseline, а molekulska težina 52.858 Da.^[8]

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

10	20	30	40	50
MKSILDGLAD	TTFRTITTDL	LYVGSNDIQY	EDIKGDMASK	LGYFPQKFPL
TSFRGSPFQE	KMTAGDNPQL	VPADQVNITE	FYNKSLSSFK	ENEENIQCGE
NFMDIECFMV	LNPSQQLAIA	VLSLTLGTFT	VLENLLVLCV	ILHSRSLRCR
PSYHFIGSLA	VADLLGSVIF	VYSFIDFHVF	HRKDSRNVFL	FKLGGVTASF
TASVGSLFLT	AIDRYISIHR	PLAYKRIVTR	PKAVVAFCLM	WTIAIVIAVL
PLLGWNCEKL	QSVCSDIFPH	IDETYLMFWI	GVTSVLLLFI	VYAYMYILWK
AHSHAVRMIQ	RGTQKSIIIH	TSEDGKVQVT	RPDQARMDIR	LAKTLVLILV
VLIICWGPLL	AIMVYDVFGK	MNKLIKTVFA	FCSMLCLLNS	TVNPIIYALR
SKDLRHAFRS	MFPSCEGTAQ	PLDNSMGDSD	CLHKHANNAA	SVHRAAESCI
KSTVKIAKVT	MSVSTDTSAE	AL

Struktura

Receptor CB₁ dijeli strukturu karakterističnu za sve receptore vezane za G-protein, posjedujući sedam transmembranskih domena, povezanih s po tri vanćelijske i unutarćelijske petlje, vanćelijskim N-terminalnim repom i unutarćelijskim C-terminalnim repom.^[9]^[10] Receptor može postojati kao homodimer ili u obliku heterodimera ili drugih GPCR oligomera različitim klasama receptora vezanih za G-protein . Posmatrani heterodimeri uključuju A_2A–CB₁, CB₁–D₂, OX₁–CB₁, dok mnogi drugi mogu biti dovoljno stabilni da postoje i in vivo.^[11] Receptor CB₁ ima alosternomodulatorsko mjesto vezanja.^[12]^[13]

Mehanizam

Receptor CB₁ je predsinapsni heteroreceptor koji modulira oslobađanje neurotransmitera kada se aktivira na dozno ovisan, stereoselektivan i na kašalj osjetljiv na toksine.^[14] Receptor CB₁ , kao aktivirani kanabinoid, prirodno se generira unutar tijela (endokanabinoidi) ili unosi u tijelo kao kanabis ili srodan sintetski spoj.

Istraživanja pokazuju da je većina receptora CB₁ spregnuta preko G_i/o proteina. Nakon aktivacije, ovaj receptor pokazuje svoje učinke uglavnom aktivacijom G_i, koja smanjuje koncentraciju unutarćelijskog cAMP-a, inhibirajući njegovu proizvodnju enzima, adenilat-ciklaza i povećava koncentraciju mitogen-aktivirane protein-kinaze (MAP-kinaze). Alternativno, u nekim rijetkim slučajevima aktivacija receptora CB₁ može biti povezana sa G_s proteinima, koji stimuliraju adenilat-ciklaze.^[11] Poznato je da cAMP služi kao drugi glasnik, povezan sa različitim ionskim kanalima, uključujući i pozitivno uticajni kalijevi kanali koji se ispravljaju prema unutra (= Kir ili IRK),^[15] i kalcijeve kanale , koji se aktiviraju interakcijom ovisnom o cAMP-u molekulama kao što su protein-kinaza A (PKA), protein-kinaza C (PKC), Raf -1, ERK, JNK, p38, c-fos, c-jun i drugi.

U smislu funkcije, inhibicija unutarćelijske ekspresije cAMP skraćuje trajanje predsinapsnih akcijskih potencijala produžavanjem ispravljajućih struja kalijevog A tipa, koje se normalno inaktiviraju pri fosforilacijama pomoću PKA. Ova inhibicija postaje sve izraženija ako se uzme u obzir učinak aktiviranih receptora CB₁, kako bi se ograničio unos kalcija u ćeliju, što se ne događa putem cAMP-a, već direktnom inhibicijom posredovanom G-proteinom. Kako je presinapsni unos kalcija uvjet za oslobađanje vezikula, ova funkcija će smanjiti neurotransmiter koji nakon otpuštanja ulazi u sinapsu.^[16] Relativna koncentracija ova dva inhibicijska mehanizma ovisi o varijajije ekspresije ionskih kanala po tipovima ćelija.

Relativni doprinos svakog od ova dva inhibitorna mehanizma ovisi o varijansi ekspresije ionskih kanala prema tipu ćelije.

Receptor CB₁ također može biti alosterni sinergijski i moduliran sintetskim ligandima^[17] na pozitivni^[18] i negativni^[19] način. In vivo izloženost THC-u narušava dugotrajno potenciranje i dovodi do smanjenja fosforiliranog CREB.^[20]

Ukratko, otkriveno je da je aktivnost receptora CB₁ povezana s određenim ionskim kanalima, na sljedeći način:^[11]

Pozitivno na unutrašnju ekspresiju i vanjske kalijeve kanale tipa A.
Negativno na vanjske kalijeve kanale D-tipa
Negativno na kalcijske kanale N-tipa i P/Q-tipa.

Ekspresija

Receptor CB₁ koriran je genom i CNR1,^[14] koji se nalazi na hromosomu 6.^[16] Opisane su dvije varijante transkripta za kodiranje različitih izoformi.^[14] CNR1 ortolozi^[21] identificirani su kod većine sisara.

Receptor CB₁ eksprimira se presinapsno i na glutaminergičnim i na GABAergičnim interneuronima i, u stvari, djeluje kao neuromodulator za inhibiranje oslobađanja glutamata i GABA. Ponovljena primjena receptorskih agonista može rezultirati internalizacijom receptora i /ili smanjenjem signalizacije proteinskih receptora.

Inverzni agonist MK-9470 omogućava stvaranje in vivo slika distribucije receptora CB₁ u ljudskom mozgu pomoću pozitronske emisione tomografije.^[22]

Ligandi

Agonisti

Selektivni

Neodređena efikasnost

Parcijalni

Endogeni

2-Arahidonil-gliceril eter

Fito/sintetski

Potpuni

Alosterni agonist

GAT228^[25]

Antagonisti

Kanabigerol
Ibipinabant
Otenabant
Tetrahidrokannabivarin
Virodhamin (Endogen CB1 antagonist i CB2 agonist)

Inverzni agonisti

Alosterni modulatori

Lipoksin A4 – endogen PAM
ZCZ-011 – PAM
Pregnenolon – endogeni NAM
Kanabidiol – NAM
Fenofibrat – NAM
GAT100 – NAM
PSNCBAM-1 – NAM
RVD-Hpα – NAM

Afinitet vezanja

	Afinitet CB₁ (K_i)	Efikasnost prema CB₁	Efikasnost CB₂ (K_i)	Efikasnost prema CB₂	Tip	Reference
Anandamid	78 nM	Parcijalni agonist	370 nM	Parcijalni agonist	Endogeni
N-Arahidonoil-dopamin	250 nM	Agonist	12000 nM	?	Endogeni	^[26]
2-Arahidonoilglicerol	58,3 nM	Potpuni agonist	145 nM	Potpuni agonist	Endogeni	^[26]
2-Arahidonil-gliceril eter	21 nM	Potpuni agonist	480 nM	Potpuni agonist	Endogeni
Tetrahidrokanabinol	10 nM	Parcijalni agonist	24 nM	Parcijalni agonist	Fitogeni	^[27]
EGCG	33600 nM	Agonist	50000+ nM	?	Fitogeni
AM-1221	52,3 nM	Agonist	0,28 nM	Agonist	Sintetski	^[28]
AM-1235	1,5 nM	Agonist	20,4 nM	Agonist	Sintetski	^[29]
AM-2232	0,28 nM	Agonist	1,48 nM	Agonist	Sintetski	^[29]
UR-144	150 nM	Potpuni agonist	1,8 nM	Potpuni agonist	Sintetski	^[30]
JWH-007	9,0 nM	Agonist	2,94 nM	Agonist	Sintetski	^[31]
JWH-015	383 nM	Agonist	13,8 nM	Agonist	Sintetski	^[31]
JWH-018	9,00 ± 5.00 nM	Potpuni agonist	2,94 ± 2,65 nM	Potpuni agonist	Sintetski	^[32]

Evolucija

Gen CNR1 koristi se kod životinja kao filogenetski marker jedarnne DNK.^[21] Ovaj gen bez introna prvi je put korišten za istraživanje filogeneze glavnih grupa sisara,^[33] i doprinijeli otkrivanju da su placentni redovi raspoređeni u pet glavnih klasa: Xenarthra, Afrotheria, Laurasiatheria, Euarchonta i Glires. CNR1 se također pokazao korisnim na nižim taksonomskim nivoima, kao što su glodari,^[34]^[35] i za identifikaciju dermoptera, kao najbližih srodnika primata.^[36]

Takođerpogledajte

Reference

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Vanjski linkovi

Ovaj članak uključuje tekst iz Nacionalne medicinske biblioteke Sjedinjenih Država, koji je u javnom vlasništvu.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000118432 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000044288 - 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.

[IUPHAR_CB1_Receptor-5] Abood M, Barth F, Bonner TI, Cabral G, Casellas P, Cravatt BF, Devane WA, Elphick MR, Felder CC, Herkenham M, Howlett AC, Kunos G, Mackie K, Mechoulam R, Pertwee RG (22. 8. 2018). "CB1 Receptor". IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology. Pristupljeno 9. 11. 2018.

[6] Thomas A, Stevenson LA, Wease KN, Price MR, Baillie G, Ross RA, Pertwee RG (decembar 2005). "Evidence that the plant cannabinoid Delta9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist". British Journal of Pharmacology. 146 (7): 917–26. doi:10.1038/sj.bjp.0706414. PMC 1751228. PMID 16205722.

[7] Pertwee RG, Thomas A, Stevenson LA, Ross RA, Varvel SA, Lichtman AH, et al. (mart 2007). "The psychoactive plant cannabinoid, Delta9-tetrahydrocannabinol, is antagonized by Delta8- and Delta9-tetrahydrocannabivarin in mice in vivo". British Journal of Pharmacology. 150 (5): 586–94. doi:10.1038/sj.bjp.0707124. PMC 2189766. PMID 17245367.

[UniProt-8] "UniProt, P21554" (jezik: engleski). Pristupljeno 7. 10. 2021.

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