Wikipedia

CNR1

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]

CNR1
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

1LVQ, 1LVR, 2B0Y, 2KOE, 2MZ3, 2MZ2, 2MZA,%%s1LVQ, 1LVR, 2B0Y, 2KOE

Identifikatori
AliasiCNR1
Vanjski ID-jeviOMIM: 114610 MGI: 104615 HomoloGene: 7273 GeneCards: CNR1
Lokacija gena (čovjek)
Hromosom 6 (čovjek)
Hrom.Hromosom 6 (čovjek)[1]
Hromosom 6 (čovjek)
Genomska lokacija za CNR1
Genomska lokacija za CNR1
Bend6q15Početak88,139,864 bp[1]
Kraj88,166,347 bp[1]
Lokacija gena (miš)
Hromosom 4 (miš)
Hrom.Hromosom 4 (miš)[2]
Hromosom 4 (miš)
Genomska lokacija za CNR1
Genomska lokacija za CNR1
Bend4 A5|4 16.28 cMPočetak33,924,593 bp[2]
Kraj33,948,831 bp[2]
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
VrsteČovjekMiš
Entrez

1268

12801

Ensembl

ENSG00000118432

ENSMUSG00000044288

UniProt

P21554

P47746

RefSeq (mRNK)
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

RefSeq (bjelančevina)
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

Lokacija (UCSC)Chr 6: 88.14 – 88.17 MbChr 4: 33.92 – 33.95 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

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

Aminokiselinska sekvenca

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

1020304050
MKSILDGLADTTFRTITTDLLYVGSNDIQYEDIKGDMASKLGYFPQKFPL
TSFRGSPFQEKMTAGDNPQLVPADQVNITEFYNKSLSSFKENEENIQCGE
NFMDIECFMVLNPSQQLAIAVLSLTLGTFTVLENLLVLCVILHSRSLRCR
PSYHFIGSLAVADLLGSVIFVYSFIDFHVFHRKDSRNVFLFKLGGVTASF
TASVGSLFLTAIDRYISIHRPLAYKRIVTRPKAVVAFCLMWTIAIVIAVL
PLLGWNCEKLQSVCSDIFPHIDETYLMFWIGVTSVLLLFIVYAYMYILWK
AHSHAVRMIQRGTQKSIIIHTSEDGKVQVTRPDQARMDIRLAKTLVLILV
VLIICWGPLLAIMVYDVFGKMNKLIKTVFAFCSMLCLLNSTVNPIIYALR
SKDLRHAFRSMFPSCEGTAQPLDNSMGDSDCLHKHANNAASVHRAAESCI
KSTVKIAKVTMSVSTDTSAEAL

Struktura

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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 A2A–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

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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 Gi/o proteina. Nakon aktivacije, ovaj receptor pokazuje svoje učinke uglavnom aktivacijom Gi, 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 Gs 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

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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

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Agonisti

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Selektivni

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Neodređena efikasnost

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Parcijalni

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Endogeni
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Fito/sintetski
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Potpuni

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Alosterni agonist

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Antagonisti

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Inverzni agonisti

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Alosterni modulatori

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Afinitet vezanja

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Afinitet CB1 (Ki) Efikasnost prema CB1 Efikasnost CB2 (Ki) 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

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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

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Reference

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  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000044288 - Ensembl, maj 2017
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Vanjski linkovi

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

Preuzeto iz "https://bs.wikipedia.org/w/index.php?title=CNR1&oldid=3371144"