P21554 · CNR1_HUMAN
- ProteinCannabinoid receptor 1
- GeneCNR1
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids472 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
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 (PubMed:1718258, PubMed:21895628, PubMed:27768894).
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 (PubMed:17895407).
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. In adipose tissue, CNR1 signaling leads to increased expression of SREBF1, ACACA and FASN genes (By similarity).
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. Peripherally modulates energy metabolism (By similarity).
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 (By similarity).
In response to cannabinoid anandamide, elicits a pro-inflammatory response in macrophages, which involves NLRP3 inflammasome activation and IL1B and IL18 secretion (By similarity).
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).
Isoform 1
Isoform 2
Isoform 3
Miscellaneous
Activity regulation
GO annotations
Keywords
- Molecular function
Enzyme and pathway databases
Protein family/group databases
Chemistry
Names & Taxonomy
Protein names
- Recommended nameCannabinoid receptor 1
- Short namesCB-R; CB1
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionP21554
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Found on presynaptic axon terminals in some GABAergic neurons in the somatosensory cortex (By similarity).
Features
Showing features for topological domain, transmembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Topological domain | 1-116 | Extracellular | ||||
Sequence: MKSILDGLADTTFRTITTDLLYVGSNDIQYEDIKGDMASKLGYFPQKFPLTSFRGSPFQEKMTAGDNPQLVPADQVNITEFYNKSLSSFKENEENIQCGENFMDIECFMVLNPSQQ | ||||||
Transmembrane | 117-142 | Helical; Name=1 | ||||
Sequence: LAIAVLSLTLGTFTVLENLLVLCVIL | ||||||
Topological domain | 143-154 | Cytoplasmic | ||||
Sequence: HSRSLRCRPSYH | ||||||
Transmembrane | 155-175 | Helical; Name=2 | ||||
Sequence: FIGSLAVADLLGSVIFVYSFI | ||||||
Topological domain | 176-187 | Extracellular | ||||
Sequence: DFHVFHRKDSRN | ||||||
Transmembrane | 188-212 | Helical; Name=3 | ||||
Sequence: VFLFKLGGVTASFTASVGSLFLTAI | ||||||
Topological domain | 213-232 | Cytoplasmic | ||||
Sequence: DRYISIHRPLAYKRIVTRPK | ||||||
Transmembrane | 233-255 | Helical; Name=4 | ||||
Sequence: AVVAFCLMWTIAIVIAVLPLLGW | ||||||
Topological domain | 256-273 | Extracellular | ||||
Sequence: NCEKLQSVCSDIFPHIDE | ||||||
Transmembrane | 274-299 | Helical; Name=5 | ||||
Sequence: TYLMFWIGVTSVLLLFIVYAYMYILW | ||||||
Topological domain | 300-344 | Cytoplasmic | ||||
Sequence: KAHSHAVRMIQRGTQKSIIIHTSEDGKVQVTRPDQARMDIRLAKT | ||||||
Transmembrane | 345-365 | Helical; Name=6 | ||||
Sequence: LVLILVVLIICWGPLLAIMVY | ||||||
Topological domain | 366-377 | Extracellular | ||||
Sequence: DVFGKMNKLIKT | ||||||
Transmembrane | 378-399 | Helical; Name=7 | ||||
Sequence: VFAFCSMLCLLNSTVNPIIYAL | ||||||
Topological domain | 400-472 | Cytoplasmic | ||||
Sequence: RSKDLRHAFRSMFPSCEGTAQPLDNSMGDSDCLHKHANNAASVHRAAESCIKSTVKIAKVTMSVSTDTSAEAL |
Keywords
- Cellular component
Disease & Variants
Involvement in disease
Obesity (OBESITY)
- Note
- DescriptionA condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.
- See alsoMIM:601665
Features
Showing features for mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 210 | 7-fold lower affinity for a synthetic agonist, CP55940, possibly due the stabilization of an inactive conformation. | ||||
Sequence: T → A | ||||||
Mutagenesis | 341-342 | Loss of activity, when assayed for GNAI1 GTPase stimulatory activity. | ||||
Sequence: LA → AL | ||||||
Mutagenesis | 415 | Loss of palmitoylation, marked loss of association with lipid rafts on the plasma membrane and loss of activity, when assayed for downstream GTP-binding and reduction in cAMP levels. | ||||
Sequence: C → A |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 539 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain, glycosylation, modified residue (large scale data), lipidation, modified residue.
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000069314 | 1-472 | UniProt | Cannabinoid receptor 1 | |||
Sequence: MKSILDGLADTTFRTITTDLLYVGSNDIQYEDIKGDMASKLGYFPQKFPLTSFRGSPFQEKMTAGDNPQLVPADQVNITEFYNKSLSSFKENEENIQCGENFMDIECFMVLNPSQQLAIAVLSLTLGTFTVLENLLVLCVILHSRSLRCRPSYHFIGSLAVADLLGSVIFVYSFIDFHVFHRKDSRNVFLFKLGGVTASFTASVGSLFLTAIDRYISIHRPLAYKRIVTRPKAVVAFCLMWTIAIVIAVLPLLGWNCEKLQSVCSDIFPHIDETYLMFWIGVTSVLLLFIVYAYMYILWKAHSHAVRMIQRGTQKSIIIHTSEDGKVQVTRPDQARMDIRLAKTLVLILVVLIICWGPLLAIMVYDVFGKMNKLIKTVFAFCSMLCLLNSTVNPIIYALRSKDLRHAFRSMFPSCEGTAQPLDNSMGDSDCLHKHANNAASVHRAAESCIKSTVKIAKVTMSVSTDTSAEAL | |||||||
Glycosylation | 77 | UniProt | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | |||||||
Glycosylation | 83 | UniProt | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | |||||||
Modified residue (large scale data) | 316 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Lipidation | 415 | UniProt | S-palmitoyl cysteine | ||||
Sequence: C | |||||||
Modified residue | 425 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 429 | UniProt | Phosphoserine | ||||
Sequence: S |
Post-translational modification
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Interaction
Subunit
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:12237474).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | P21554 | ADORA2A P29274 | 8 | EBI-2909859, EBI-2902702 | |
BINARY | P21554 | CNR1 P21554 | 8 | EBI-2909859, EBI-2909859 |
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for region.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 2-23 | Required for mitochondrial localization | ||||
Sequence: KSILDGLADTTFRTITTDLLYV |
Sequence similarities
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Protein family/group databases
Sequence & Isoforms
- Sequence statusComplete
This entry describes 3 isoforms produced by Alternative splicing.
P21554-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- SynonymsLong
- Length472
- Mass (Da)52,858
- Last updated1991-05-01 v1
- Checksum1D2E49061D12ABF2
P21554-2
- Name2
- SynonymsCB1a, Short
- Differences from canonical
- 1-89: MKSILDGLADTTFRTITTDLLYVGSNDIQYEDIKGDMASKLGYFPQKFPLTSFRGSPFQEKMTAGDNPQLVPADQVNITEFYNKSLSSF → MALQIPPSAPSPLTSCTWAQMTFSTKTS
P21554-3
- Name3
- SynonymsCB1b
- Differences from canonical
- 22-54: Missing
Computationally mapped potential isoform sequences
There are 2 potential isoforms mapped to this entry
Features
Showing features for alternative sequence, sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_001868 | 1-89 | in isoform 2 | |||
Sequence: MKSILDGLADTTFRTITTDLLYVGSNDIQYEDIKGDMASKLGYFPQKFPLTSFRGSPFQEKMTAGDNPQLVPADQVNITEFYNKSLSSF → MALQIPPSAPSPLTSCTWAQMTFSTKTS | ||||||
Alternative sequence | VSP_016529 | 22-54 | in isoform 3 | |||
Sequence: Missing | ||||||
Sequence conflict | 94 | in Ref. 12; AAH95513 | ||||
Sequence: E → G | ||||||
Sequence conflict | 103 | in Ref. 12; AAH95513 | ||||
Sequence: M → I | ||||||
Sequence conflict | 149 | in Ref. 12; AAH95513 | ||||
Sequence: C → R | ||||||
Sequence conflict | 200 | in Ref. 5; AAD34320 | ||||
Sequence: F → L | ||||||
Sequence conflict | 216 | in Ref. 5; AAD34320 | ||||
Sequence: I → V | ||||||
Sequence conflict | 246 | in Ref. 5; AAD34320 | ||||
Sequence: V → A | ||||||
Sequence conflict | 298 | in Ref. 12; AAH95513 | ||||
Sequence: L → P | ||||||
Sequence conflict | 332 | in Ref. 12; AAI00972 | ||||
Sequence: P → S |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
X54937 EMBL· GenBank· DDBJ | CAA38699.1 EMBL· GenBank· DDBJ | mRNA | ||
X81120 EMBL· GenBank· DDBJ | CAA57018.1 EMBL· GenBank· DDBJ | mRNA | ||
X81121 EMBL· GenBank· DDBJ | CAA57019.1 EMBL· GenBank· DDBJ | mRNA | ||
AY766182 EMBL· GenBank· DDBJ | AAV35030.1 EMBL· GenBank· DDBJ | mRNA | ||
AF107262 EMBL· GenBank· DDBJ | AAD34320.1 EMBL· GenBank· DDBJ | mRNA | ||
U73304 EMBL· GenBank· DDBJ | AAB18200.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
DQ067455 EMBL· GenBank· DDBJ | AAY68486.1 EMBL· GenBank· DDBJ | mRNA | ||
AY225225 EMBL· GenBank· DDBJ | AAO67710.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AL136096 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
AK313908 EMBL· GenBank· DDBJ | BAG36631.1 EMBL· GenBank· DDBJ | mRNA | ||
CH471051 EMBL· GenBank· DDBJ | EAW48574.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471051 EMBL· GenBank· DDBJ | EAW48575.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471051 EMBL· GenBank· DDBJ | EAW48576.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC074811 EMBL· GenBank· DDBJ | AAH74811.1 EMBL· GenBank· DDBJ | mRNA | ||
BC074812 EMBL· GenBank· DDBJ | AAH74812.1 EMBL· GenBank· DDBJ | mRNA | ||
BC095513 EMBL· GenBank· DDBJ | AAH95513.1 EMBL· GenBank· DDBJ | mRNA | ||
BC100968 EMBL· GenBank· DDBJ | AAI00969.1 EMBL· GenBank· DDBJ | mRNA | ||
BC100969 EMBL· GenBank· DDBJ | AAI00970.1 EMBL· GenBank· DDBJ | mRNA | ||
BC100970 EMBL· GenBank· DDBJ | AAI00971.1 EMBL· GenBank· DDBJ | mRNA | ||
BC100971 EMBL· GenBank· DDBJ | AAI00972.1 EMBL· GenBank· DDBJ | mRNA |