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Protein

Cannabinoid receptor 1

Gene

Cnr1

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

G-protein coupled receptor for cannabinoids, including endocannabinoids (eCBs), such as N-arachidonoylethanolamide (also called anandamide or AEA) and 2-arachidonoylglycerol (2-AG) (PubMed:2165569). Mediates many cannabinoid-induced effects, acting, among others, on food intake, memory loss, gastrointestinal motility, catalepsy, ambulatory activity, anxiety, chronic pain. Signaling typically involves reduction in cyclic AMP. In the hypothalamus, may have a dual effect on mitochondrial respiration depending upon the agonist dose and possibly upon the cell type. Increases respiration at low doses, while decreases respiration at high doses. At high doses, CNR1 signal transduction involves G-protein alpha-i protein activation and subsequent inhibition of mitochondrial soluble adenylate cyclase, decrease in cyclic AMP concentration, inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system, including NDUFS2. In the hypothalamus, inhibits leptin-induced reactive oxygen species (ROS) formation and mediates cannabinoid-induced increase in SREBF1 and FASN gene expression. In response to cannabinoids, drives the release of orexigenic beta-endorphin, but not that of melanocyte-stimulating hormone alpha/alpha-MSH, from hypothalamic POMC neurons, hence promoting food intake. In the hippocampus, regulates cellular respiration and energy production in response to cannabinoids. Involved in cannabinoid-dependent depolarization-induced suppression of inhibition (DSI), a process in which depolarization of CA1 postsynaptic pyramidal neurons mobilizes eCBs, which retrogradely activate presynaptic CB1 receptors, transiently decreasing GABAergic inhibitory neurotransmission. Also reduces excitatory synaptic transmission (By similarity). In superior cervical ganglions and cerebral vascular smooth muscle cells, inhibits voltage-gated Ca2+ channels in a constitutive, as well as agonist-dependent manner (By similarity). Induces leptin production in adipocytes and reduces LRP2-mediated leptin clearance in the kidney, hence participating in hyperleptinemia. In adipose tissue, CNR1 signaling leads to increased expression of SREBF1, ACACA and FASN genes. In the liver, activation by endocannabinoids leads to increased de novo lipogenesis and reduced fatty acid catabolism, associated with increased expression of SREBF1/SREBP-1, GCK, ACACA, ACACB and FASN genes. May also affect de novo cholesterol synthesis and HDL-cholesteryl ether uptake (By similarity). Peripherally modulates energy metabolism. In high carbohydrate diet-induced obesity, may decrease the expression of mitochondrial dihydrolipoyl dehydrogenase/DLD in striated muscles, as well as that of selected glucose/ pyruvate metabolic enzymes, hence affecting energy expenditure through mitochondrial metabolism (PubMed:26671069). In response to cannabinoid anandamide, elicits a proinflammatory response in macrophages, which involves NLRP3 inflammasome activation and IL1B and IL18 secretion. In macrophages infiltrating pancreatic islets, this process may participate in the progression of type-2 diabetes and associated loss of pancreatic beta-cells (PubMed:23955712).By similarity3 Publications

Miscellaneous

High-fat diet also increases the hepatic levels of CNR1 ligand anandamide, but not that of 2-arachidonoylglycerol.By similarity

GO - Molecular functioni

  • cannabinoid receptor activity Source: RGD
  • drug binding Source: RGD

GO - Biological processi

  • adenylate cyclase-modulating G-protein coupled receptor signaling pathway Source: UniProtKB
  • aging Source: RGD
  • axonal fasciculation Source: Ensembl
  • glucose homeostasis Source: Ensembl
  • G-protein coupled receptor signaling pathway Source: RGD
  • learning or memory Source: RGD
  • maternal process involved in female pregnancy Source: RGD
  • memory Source: RGD
  • negative regulation of action potential Source: RGD
  • negative regulation of blood pressure Source: RGD
  • negative regulation of dopamine secretion Source: RGD
  • negative regulation of fatty acid beta-oxidation Source: RGD
  • negative regulation of ion transport Source: RGD
  • negative regulation of mast cell activation Source: RGD
  • negative regulation of nitric-oxide synthase activity Source: RGD
  • positive regulation of acute inflammatory response to antigenic stimulus Source: RGD
  • positive regulation of apoptotic process Source: RGD
  • positive regulation of blood pressure Source: RGD
  • positive regulation of fever generation Source: RGD
  • positive regulation of neuron projection development Source: RGD
  • regulation of feeding behavior Source: RGD
  • regulation of insulin secretion Source: RGD
  • regulation of lipid metabolic process Source: RGD
  • regulation of penile erection Source: RGD
  • regulation of synaptic transmission, GABAergic Source: RGD
  • regulation of synaptic transmission, glutamatergic Source: RGD
  • response to cocaine Source: RGD
  • response to ethanol Source: RGD
  • response to lipopolysaccharide Source: RGD
  • response to morphine Source: RGD
  • response to nicotine Source: RGD
  • response to nutrient Source: RGD
  • sensory perception of pain Source: RGD
  • spermatogenesis Source: RGD
  • trans-synaptic signaling by endocannabinoid, modulating synaptic transmission Source: Ensembl

Keywordsi

Molecular functionG-protein coupled receptor, Receptor, Transducer

Enzyme and pathway databases

ReactomeiR-RNO-373076. Class A/1 (Rhodopsin-like receptors).
R-RNO-418594. G alpha (i) signalling events.

Names & Taxonomyi

Protein namesi
Recommended name:
Cannabinoid receptor 1
Short name:
CB-R
Short name:
CB1
Alternative name(s):
Brain-type cannabinoid receptor
Gene namesi
Name:Cnr1
Synonyms:Skr61 Publication
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 5

Organism-specific databases

RGDi2369. Cnr1.

Subcellular locationi

  • Cell membrane By similarity; Multi-pass membrane protein By similarity
  • Mitochondrion outer membrane By similarity
  • Cell projectionaxon 1 Publication

  • Note: Unexpectedly, in the mitochondria, the C-terminus is located in the mitochondrial intermembrane space, a compartment topologically considered as extracellular. In canonical seven-transmembrane G-protein coupled receptors, the C-terminus is cytosolic (By similarity). In interneurons, found on the membrane of cytoplasmic compartments, some of which could be elements of the endosome-lysosome system and multivesicular bodies (PubMed:16033894). Found on presynaptic axon terminals in some GABAergic neurons in the somatosensory cortex (PubMed:16033894).By similarity1 Publication

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 117ExtracellularBy similarityAdd BLAST117
Transmembranei118 – 143Helical; Name=1By similarityAdd BLAST26
Topological domaini144 – 155CytoplasmicBy similarityAdd BLAST12
Transmembranei156 – 176Helical; Name=2By similarityAdd BLAST21
Topological domaini177 – 188ExtracellularBy similarityAdd BLAST12
Transmembranei189 – 213Helical; Name=3By similarityAdd BLAST25
Topological domaini214 – 233CytoplasmicBy similarityAdd BLAST20
Transmembranei234 – 256Helical; Name=4By similarityAdd BLAST23
Topological domaini257 – 274ExtracellularBy similarityAdd BLAST18
Transmembranei275 – 300Helical; Name=5By similarityAdd BLAST26
Topological domaini301 – 345CytoplasmicBy similarityAdd BLAST45
Transmembranei346 – 366Helical; Name=6By similarityAdd BLAST21
Topological domaini367 – 378ExtracellularBy similarityAdd BLAST12
Transmembranei379 – 400Helical; Name=7By similarityAdd BLAST22
Topological domaini401 – 473CytoplasmicBy similarityAdd BLAST73

GO - Cellular componenti

Keywords - Cellular componenti

Cell membrane, Cell projection, Membrane, Mitochondrion, Mitochondrion outer membrane

Pathology & Biotechi

Chemistry databases

ChEMBLiCHEMBL3571.
GuidetoPHARMACOLOGYi56.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000693181 – 473Cannabinoid receptor 1Add BLAST473

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi78N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi84N-linked (GlcNAc...) asparagineSequence analysis1
Lipidationi416S-palmitoyl cysteine1 Publication1
Modified residuei426PhosphoserineBy similarity1
Modified residuei430PhosphoserineBy similarity1

Post-translational modificationi

Palmitoylation at Cys-416 is important for recruitment at both plasma membrane and lipid rafts and association with G protein alpha subunits.1 Publication

Keywords - PTMi

Glycoprotein, Lipoprotein, Palmitate, Phosphoprotein

Proteomic databases

PaxDbiP20272.
PRIDEiP20272.

PTM databases

iPTMnetiP20272.
PhosphoSitePlusiP20272.
SwissPalmiP20272.

Expressioni

Tissue specificityi

Expressed in the brain, in the striatum, medial septum, descending arm of the band of Broca, the amygdaloid nucleus, the hippocampus and cortex (at protein level). High levels in the lateral striatum. In rostral brain regions, high expression levels in the dorsal lateral striatum, while in the caudal brain regions, high levels are observed in the ventral lateral striatum (PubMed:2165569, PubMed:10362691, PubMed:10891614, PubMed:16033894). Expressed in monocytes/macrophages (at protein level) (PubMed:23955712). Expressed in striated muscles and in vascular smooth muscles cells (at protein level) (PubMed:10362691, PubMed:26671069).6 Publications

Gene expression databases

BgeeiENSRNOG00000008223.
GenevisibleiP20272. RN.

Interactioni

Subunit structurei

Interacts (via C-terminus) with CNRIP1 (PubMed:17895407). Associates with G protein alpha subunits, including G(i) alpha-1/GNAI1, G(i) alpha-3/GNAI3 and G(o) alpha/GNAO1; palmitoylation is important for interaction with GNAI3 and GNAO1 (PubMed:21895628).2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Adora2aP305433EBI-2909800,EBI-2902822

Protein-protein interaction databases

BioGridi247288. 1 interactor.
IntActiP20272. 2 interactors.
MINTiMINT-7266592.
STRINGi10116.ENSRNOP00000010850.

Chemistry databases

BindingDBiP20272.

Structurei

3D structure databases

ProteinModelPortaliP20272.
SMRiP20272.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni2 – 23Required for mitochondrial localizationBy similarityAdd BLAST22

Sequence similaritiesi

Belongs to the G-protein coupled receptor 1 family.PROSITE-ProRule annotation

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG3656. Eukaryota.
ENOG410XRW9. LUCA.
GeneTreeiENSGT00760000118804.
HOGENOMiHOG000049272.
HOVERGENiHBG051045.
InParanoidiP20272.
KOiK04277.
OMAiTRMDIRL.
OrthoDBiEOG091G05O3.
PhylomeDBiP20272.
TreeFamiTF330052.

Family and domain databases

CDDicd15340. 7tmA_CB1. 1 hit.
InterProiView protein in InterPro
IPR000810. Canbinoid_rcpt_1.
IPR002230. Cnbnoid_rcpt.
IPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
PANTHERiPTHR22750:SF57. PTHR22750:SF57. 1 hit.
PfamiView protein in Pfam
PF00001. 7tm_1. 1 hit.
PIRSFiPIRSF037995. Cnoid_rcpt_1. 1 hit.
PRINTSiPR00522. CANABINOID1R.
PR00362. CANNABINOIDR.
PR00237. GPCRRHODOPSN.
SMARTiView protein in SMART
SM01381. 7TM_GPCR_Srsx. 1 hit.
PROSITEiView protein in PROSITE
PS00237. G_PROTEIN_RECEP_F1_1. 1 hit.
PS50262. G_PROTEIN_RECEP_F1_2. 1 hit.

Sequencei

Sequence statusi: Complete.

P20272-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MKSILDGLAD TTFRTITTDL LYVGSNDIQY EDIKGDMASK LGYFPQKFPL
60 70 80 90 100
TSFRGSPFQE KMTAGDNSPL VPAGDTTNIT EFYNKSLSSF KENEENIQCG
110 120 130 140 150
ENFMDMECFM ILNPSQQLAI AVLSLTLGTF TVLENLLVLC VILHSRSLRC
160 170 180 190 200
RPSYHFIGSL AVADLLGSVI FVYSFVDFHV FHRKDSPNVF LFKLGGVTAS
210 220 230 240 250
FTASVGSLFL TAIDRYISIH RPLAYKRIVT RPKAVVAFCL MWTIAIVIAV
260 270 280 290 300
LPLLGWNCKK LQSVCSDIFP LIDETYLMFW IGVTSVLLLF IVYAYMYILW
310 320 330 340 350
KAHSHAVRMI QRGTQKSIII HTSEDGKVQV TRPDQARMDI RLAKTLVLIL
360 370 380 390 400
VVLIICWGPL LAIMVYDVFG KMNKLIKTVF AFCSMLCLLN STVNPIIYAL
410 420 430 440 450
RSKDLRHAFR SMFPSCEGTA QPLDNSMGDS DCLHKHANNT ASMHRAAESC
460 470
IKSTVKIAKV TMSVSTDTSA EAL
Length:473
Mass (Da):52,845
Last modified:February 1, 1991 - v1
Checksum:iE59A66AFE17B646C
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X55812 mRNA. Translation: CAA39332.1.
U40395 mRNA. Translation: AAA99067.1.
PIRiA33117.
RefSeqiNP_036916.1. NM_012784.4.
XP_006238046.1. XM_006237984.3.
XP_017448640.1. XM_017593151.1.
UniGeneiRn.89774.

Genome annotation databases

EnsembliENSRNOT00000010850; ENSRNOP00000010850; ENSRNOG00000008223.
GeneIDi25248.
KEGGirno:25248.
UCSCiRGD:2369. rat.

Similar proteinsi

Entry informationi

Entry nameiCNR1_RAT
AccessioniPrimary (citable) accession number: P20272
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1991
Last sequence update: February 1, 1991
Last modified: August 30, 2017
This is version 139 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. 7-transmembrane G-linked receptors
    List of 7-transmembrane G-linked receptor entries
  2. SIMILARITY comments
    Index of protein domains and families