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Protein

Cannabinoid receptor 1

Gene

Cnr1

Organism
Mus musculus (Mouse)
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:9888857, PubMed:22388959). Mediates many cannabinoid-induced effects, acting, among others, on food intake, memory loss, gastrointestinal motility, catalepsy, ambulatory activity, anxiety, chronic pain (PubMed:9888857, PubMed:27828947). Signaling typically involves reduction in cyclic AMP (PubMed:8832654, PubMed:27828947). Signaling typically involves reduction in cyclic AMP (By similarity). 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 (PubMed:25707796, PubMed:27828947). 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 (PubMed:27828947). In the hypothalamus, inhibits leptin-induced reactive oxygen species (ROS) formation and mediates cannabinoid-induced increase in SREBF1 and FASN gene expression (PubMed:25869131). 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 (PubMed:25707796). 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 (PubMed:22388959). Also reduces excitatory synaptic transmission (PubMed:27828947). 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). In cerebral vascular smooth muscle cells, cannabinoid-induced inhibition of voltage-gated Ca2+ channels leads to vasodilation and decreased vascular tone (By similarity). Induces leptin production in adipocytes and reduces LRP2-mediated leptin clearance in the kidney, hence participating in hyperleptinemia (PubMed:22841573). In adipose tissue, CNR1 signaling leads to increased expression of SREBF1, ACACA and FASN genes (PubMed:15864349). 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 (PubMed:15864349, PubMed:21987372). May also affect de novo cholesterol synthesis and HDL-cholesteryl ether uptake (PubMed:21987372). 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 similarity11 Publications

Miscellaneous

High-fat diet also increases the hepatic levels of CNR1 ligand anandamide, but not that of 2-arachidonoylglycerol.1 Publication

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionG-protein coupled receptor, Receptor, Transducer

Enzyme and pathway databases

ReactomeiR-MMU-373076. Class A/1 (Rhodopsin-like receptors).
R-MMU-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
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 4

Organism-specific databases

MGIiMGI:104615. Cnr1.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 121ExtracellularBy similarityAdd BLAST121
Transmembranei122 – 142HelicalBy similarityAdd BLAST21
Topological domaini143 – 155CytoplasmicBy similarityAdd BLAST13
Transmembranei156 – 176HelicalBy similarityAdd BLAST21
Topological domaini177 – 188ExtracellularBy similarityAdd BLAST12
Transmembranei189 – 209HelicalBy similarityAdd BLAST21
Topological domaini210 – 233CytoplasmicBy similarityAdd BLAST24
Transmembranei234 – 254HelicalBy similarityAdd BLAST21
Topological domaini255 – 278ExtracellularBy similarityAdd BLAST24
Transmembranei279 – 299HelicalBy similarityAdd BLAST21
Topological domaini300 – 345CytoplasmicBy similarityAdd BLAST46
Transmembranei346 – 366HelicalBy similarityAdd BLAST21
Topological domaini367 – 378ExtracellularBy similarityAdd BLAST12
Transmembranei379 – 399HelicalBy similarityAdd BLAST21
Topological domaini400 – 473CytoplasmicBy similarityAdd BLAST74

Keywords - Cellular componenti

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

Pathology & Biotechi

Involvement in diseasei

May contribute to the development of diet-induced obesity and several obesity-associated features, such as dyslipidemia and liver steatosis, regulating peripheral lipogenesis, energy expenditure and feeding behavior. In the liver, mediates cannabinoid-induced de novo lipogenesis and reduces fatty acid catabolism (PubMed:15864349, PubMed:21987372). In muscles, affects energy expenditure through mitochondrial metabolism (PubMed:22841573, PubMed:26671069). Induces leptin production by adipocytes and reduces LRP2-mediated leptin clearance in the kidney. The resulting hyperleptinemia causes resistance to the anorexic and weight-reducing effects of leptin (PubMed:22841573). In response to cannabinoids, drives the release of orexigenic beta-endorphin from hypothalamic POMC neurons, hence promoting food intake (PubMed:25707796). The use of peripherally-restricted inverse agonists in diet-induced obese mice reduces appetite, body weight, hepatic steatosis, and insulin resistance (PubMed:22841573).5 Publications

Disruption phenotypei

No visible phenotype, although mutant mice present a mild impairment in the adaptation to new environment. Mutant mice do not respond to cannabinoids, such as anandamide. The acute effects of opiates are not affected, but the reinforcing properties of morphine and the severity of the withdrawal syndrome are strongly reduced (PubMed:9888857). On high-fat diet, mutant mice remain lean, their metabolic and hormonal profile are unchanged, and they do not develop fatty liver, despite having caloric intake similar to that of wild-type mice (PubMed:15864349).2 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi2 – 23Missing : Loss of mitochondrial localization. Loss of cannabinoid-induced reduction of respiration, mitochondrial mobility, synaptic transmission and memory formation. No effect on MAPK/ERK signaling, nor on G protein activation. 1 PublicationAdd BLAST22

Keywords - Diseasei

Obesity

Chemistry databases

ChEMBLiCHEMBL3037.
GuidetoPHARMACOLOGYi56.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000693161 – 473Cannabinoid receptor 1Add BLAST473

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi78N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi84N-linked (GlcNAc...) asparagineSequence analysis1
Lipidationi416S-palmitoyl cysteineBy similarity1
Modified residuei426PhosphoserineCombined sources1
Modified residuei430PhosphoserineCombined sources1

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.By similarity

Keywords - PTMi

Glycoprotein, Lipoprotein, Palmitate, Phosphoprotein

Proteomic databases

MaxQBiP47746.
PaxDbiP47746.
PeptideAtlasiP47746.
PRIDEiP47746.

PTM databases

iPTMnetiP47746.
PhosphoSitePlusiP47746.
SwissPalmiP47746.

Expressioni

Tissue specificityi

Expressed in brain neurons (at protein level) (PubMed:22388959). Detected throughout the striatum, cortex and hippocampus, with highest levels in the lateral striatum (PubMed:15606779, PubMed:10891614, PubMed:22388959). 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:10891614). Expressed in neurons (PubMed:10891614). In the hypothalamus, expressed in both GABAergic and glutamatergic presynaptic terminals of POMC neurons (at protein level) (PubMed:25869131, PubMed:25707796). Expressed in striated muscles, including skeletal muscles (gastrocnemius and rectus abdominis) and myocardium (at protein level) (PubMed:26671069, PubMed:27826249). Expressed in the liver, with highest levels in Kupffer cells and lower levels in endothelial cells as well as hepatocytes, particularly in perivascular areas (at protein level) (PubMed:15864349, PubMed:21987372). The hepatic expression level is up-regulated in obese mice compared to lean animals (PubMed:21987372).9 Publications

Inductioni

Up-regulated by endocannabinoid anandamide/AEA (PubMed:21987372, PubMed:23955712). Down-regulated by IL1B (PubMed:23955712). Up-regulated in the liver of animals on a high-fat diet compared to regular diet (PubMed:15864349, PubMed:21987372).3 Publications

Gene expression databases

BgeeiENSMUSG00000044288.
CleanExiMM_CNR1.
GenevisibleiP47746. MM.

Interactioni

Subunit structurei

Interacts (via C-terminus) with CNRIP1 (By similarity). 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:27828947).By similarity1 Publication

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000055797.

Chemistry databases

BindingDBiP47746.

Structurei

3D structure databases

ProteinModelPortaliP47746.
SMRiP47746.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni2 – 23Required for mitochondrial localization1 PublicationAdd 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.
InParanoidiP47746.
KOiK04277.
OMAiTRMDIRL.
OrthoDBiEOG091G05O3.
PhylomeDBiP47746.
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.

P47746-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MKSILDGLAD TTFRTITTDL LYVGSNDIQY EDIKGDMASK LGYFPQKFPL
60 70 80 90 100
TSFRGSPFQE KMTAGDNSPL VPAGDTTNIT EFYNKSLSSF KENEDNIQCG
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):52,831
Last modified:February 1, 1996 - v1
Checksum:iE504168191CB6429
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti9A → G in AAA57202 (PubMed:8777318).Curated1
Sequence conflicti115S → R in AAA57202 (PubMed:8777318).Curated1
Sequence conflicti211T → R in AAA57202 (PubMed:8777318).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U17985 mRNA. Translation: AAA57202.1.
U40709 mRNA. Translation: AAA91176.1.
Y18374 Genomic DNA. Translation: CAB42647.1.
AY522555 Genomic DNA. Translation: AAS91801.1.
AY522554 mRNA. Translation: AAS91800.1.
U22948 Genomic DNA. Translation: AAA64413.1.
AF153345 mRNA. Translation: AAD34624.1.
AK139417 mRNA. Translation: BAE24003.1.
BC070447 mRNA. Translation: AAH70447.1.
BC079564 mRNA. Translation: AAH79564.1.
CCDSiCCDS18025.1.
RefSeqiNP_031752.1. NM_007726.3.
XP_006537654.1. XM_006537591.2.
XP_006537655.1. XM_006537592.3.
XP_006537656.1. XM_006537593.3.
XP_006537657.1. XM_006537594.2.
XP_006537658.1. XM_006537595.2.
XP_017175428.1. XM_017319939.1.
UniGeneiMm.7992.

Genome annotation databases

EnsembliENSMUST00000057188; ENSMUSP00000055797; ENSMUSG00000044288.
ENSMUST00000084736; ENSMUSP00000081787; ENSMUSG00000044288.
GeneIDi12801.
KEGGimmu:12801.
UCSCiuc008sfw.1. mouse.

Similar proteinsi

Entry informationi

Entry nameiCNR1_MOUSE
AccessioniPrimary (citable) accession number: P47746
Secondary accession number(s): Q5SF33
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: February 1, 1996
Last modified: September 27, 2017
This is version 144 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. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  3. SIMILARITY comments
    Index of protein domains and families