P21554 · CNR1_HUMAN

  • Protein
    Cannabinoid receptor 1
  • Gene
    CNR1
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at protein level
  • Annotation score
    5/5

Function

function

G-protein coupled receptor for endogenous cannabinoids (eCBs), including N-arachidonoylethanolamide (also called anandamide or AEA) and 2-arachidonoylglycerol (2-AG), as well as phytocannabinoids, such as delta9-tetrahydrocannabinol (THC) (PubMed:15620723, PubMed:27768894, PubMed:27851727).
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

Binds both 2-arachidonoylglycerol (2-AG) and anandamide.

Isoform 2

Only binds 2-arachidonoylglycerol (2-AG) with high affinity. Contrary to its effect on isoform 1, 2-AG behaves as an inverse agonist on isoform 2 in assays measuring GTP binding to membranes.

Isoform 3

Only binds 2-arachidonoylglycerol (2-AG) with high affinity. Contrary to its effect on isoform 1, 2-AG behaves as an inverse agonist on isoform 3 in assays measuring GTP binding to membranes.

Miscellaneous

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

Activity regulation

Hemopressin, a peptide derived from hemoglobin subunit alpha (HBA1 and/or HBA2), acts as an antagonist peptide: hemopressin-binding efficiently blocks cannabinoid receptor CNR1 and subsequent signaling.

GO annotations

AspectTerm
Cellular Componentactin cytoskeleton
Cellular Componentcytoplasm
Cellular ComponentGABA-ergic synapse
Cellular Componentglutamatergic synapse
Cellular Componentgrowth cone
Cellular Componentmembrane raft
Cellular Componentmitochondrial outer membrane
Cellular Componentplasma membrane
Cellular Componentpresynaptic membrane
Molecular Functioncannabinoid receptor activity
Molecular FunctionG protein-coupled receptor activity
Molecular Functionidentical protein binding
Biological Processadenylate cyclase-activating G protein-coupled receptor signaling pathway
Biological Processadenylate cyclase-modulating G protein-coupled receptor signaling pathway
Biological Processaxonal fasciculation
Biological Processcannabinoid signaling pathway
Biological ProcessG protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger
Biological Processglucose homeostasis
Biological Processmaternal process involved in female pregnancy
Biological Processmemory
Biological Processnegative regulation of action potential
Biological Processnegative regulation of blood pressure
Biological Processnegative regulation of dopamine secretion
Biological Processnegative regulation of fatty acid beta-oxidation
Biological Processnegative regulation of mast cell activation
Biological Processnegative regulation of serotonin secretion
Biological Processpositive regulation of acute inflammatory response to antigenic stimulus
Biological Processpositive regulation of apoptotic process
Biological Processpositive regulation of blood pressure
Biological Processpositive regulation of fever generation
Biological Processpositive regulation of neuron projection development
Biological Processregulation of feeding behavior
Biological Processregulation of insulin secretion
Biological Processregulation of metabolic process
Biological Processregulation of penile erection
Biological Processregulation of presynaptic cytosolic calcium ion concentration
Biological Processregulation of synaptic transmission, GABAergic
Biological Processregulation of synaptic transmission, glutamatergic
Biological Processresponse to cocaine
Biological Processresponse to ethanol
Biological Processresponse to lipopolysaccharide
Biological Processresponse to nicotine
Biological Processresponse to nutrient
Biological Processretrograde trans-synaptic signaling by endocannabinoid
Biological Processspermatogenesis
Biological Processtrans-synaptic signaling by endocannabinoid, modulating synaptic transmission

Keywords

Enzyme and pathway databases

Protein family/group databases

Chemistry

Names & Taxonomy

Protein names

  • Recommended name
    Cannabinoid receptor 1
  • Short names
    CB-R; CB1
  • Alternative names
    • CANN6

Gene names

    • Name
      CNR1
    • Synonyms
      CNR

Organism names

  • Taxonomic identifier
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo

Accessions

  • Primary accession
    P21554
  • Secondary accessions
    • B2R9T4
    • E1P512
    • Q13949
    • Q495Z0
    • Q4PLI4

Proteomes

Organism-specific databases

Subcellular Location

Cell membrane
; Multi-pass membrane protein
Membrane raft
Cell projection, axon
Presynapse
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).
Found on presynaptic axon terminals in some GABAergic neurons in the somatosensory cortex (By similarity).

Features

Showing features for topological domain, transmembrane.

TypeIDPosition(s)Description
Topological domain1-116Extracellular
Transmembrane117-142Helical; Name=1
Topological domain143-154Cytoplasmic
Transmembrane155-175Helical; Name=2
Topological domain176-187Extracellular
Transmembrane188-212Helical; Name=3
Topological domain213-232Cytoplasmic
Transmembrane233-255Helical; Name=4
Topological domain256-273Extracellular
Transmembrane274-299Helical; Name=5
Topological domain300-344Cytoplasmic
Transmembrane345-365Helical; Name=6
Topological domain366-377Extracellular
Transmembrane378-399Helical; Name=7
Topological domain400-472Cytoplasmic

Keywords

Disease & Variants

Involvement in disease

Obesity (OBESITY)

  • Note
    • The protein represented in this entry may be involved in disease pathogenesis. 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. CNR1 inverse agonists have been shown to reduce body weight and improve metabolic abnormalities in obese subjects, although adverse neuropsychiatric effects, including anxiety, irritability, and depressed mood, halted their therapeutic development (PubMed:18177726). In obese mice, peripherally restricted CNR1 inverse agonists have been shown to normalize metabolic abnormalities, including insulin resistance and fatty liver, and to reverse leptin resistance
  • Description
    A 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 also
    MIM:601665
  • Dysfunction of the endogenous cannabinoid system including CNR1 has been implicated in the pathogenesis of a number of central nervous system disorders, including Huntington disease, Parkinson disease, and Alzheimer disease (PubMed:32549916). In post-mortem brains from Huntington disease patients, a progressive CNR1 loss has been observed in the caudate nucleus, putamen, and substantia nigra pars reticulata, and altered expression and abnormal endocannabinoid levels precede motor symptoms in a disease mouse model (PubMed:10828533, PubMed:19524019, PubMed:8255419). In Parkinson disease, low CNR1 expression in mid-superior frontal gyrus and mid-cingulate cortex has been associated with poor mind, poor executive functioning and poor episode memory, while patients with more severe visuospatial dysfunction showed decreased receptor availability in the precuneus, mid-cingulate, supplementary motor cortex, inferior orbitofrontal gyrus and thalamus (PubMed:31342135). In an animal model for Alzheimer disease, CNR1 heterozygous deletion has been associated with decreased levels of postsynaptic density protein 95 (DLG4/PSD95) and accelerated memory impairment, suggesting synaptic dysfunction and a crucial role for CNR1 in the progression of disease symptoms (PubMed:10828533, PubMed:19524019, PubMed:30096288, PubMed:31342135, PubMed:8255419)

Features

Showing features for mutagenesis.

TypeIDPosition(s)Description
Mutagenesis2107-fold lower affinity for a synthetic agonist, CP55940, possibly due the stabilization of an inactive conformation.
Mutagenesis341-342Loss of activity, when assayed for GNAI1 GTPase stimulatory activity.
Mutagenesis415Loss 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.

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.

Go to variant viewer

Keywords

Organism-specific databases

Miscellaneous

Chemistry

Genetic variation databases

PTM/Processing

Features

Showing features for chain, glycosylation, modified residue (large scale data), lipidation, modified residue.

TypeIDPosition(s)SourceDescription
ChainPRO_00000693141-472UniProtCannabinoid receptor 1
Glycosylation77UniProtN-linked (GlcNAc...) asparagine
Glycosylation83UniProtN-linked (GlcNAc...) asparagine
Modified residue (large scale data)316PRIDEPhosphoserine
Lipidation415UniProtS-palmitoyl cysteine
Modified residue425UniProtPhosphoserine
Modified residue429UniProtPhosphoserine

Post-translational modification

Palmitoylation at Cys-415 is important for recruitment at plasma membrane and lipid rafts and association with G protein alpha subunits.

Keywords

Proteomic databases

PTM databases

Expression

Tissue specificity

Widely expressed, with highest levels in fetal and adult brain. Expression levels of isoform 2 and isoform 3 are much lower than those of isoform 1.

Induction

Up-regulated by endocannabinoid anandamide.

Gene expression databases

Organism-specific databases

Interaction

Subunit

Interacts (via C-terminus) with CNRIP1; this interaction attenuates constitutive, but not agonist-dependent, inhibition of voltage-gated Ca2+ channels in neurons (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:12237474).

Binary interactions

TypeEntry 1Entry 2Number of experimentsIntact
BINARY P21554ADORA2A P292748EBI-2909859, EBI-2902702
BINARY P21554CNR1 P215548EBI-2909859, EBI-2909859

Protein-protein interaction databases

Chemistry

Miscellaneous

Family & Domains

Features

Showing features for region.

TypeIDPosition(s)Description
Region2-23Required for mitochondrial localization

Sequence similarities

Belongs to the G-protein coupled receptor 1 family.

Keywords

Phylogenomic databases

Family and domain databases

Protein family/group databases

Sequence & Isoforms

Align isoforms (3)
  • Sequence status
    Complete

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.

  • Name
    1
  • Synonyms
    Long
  • See also
    sequence in UniParc or sequence clusters in UniRef
  • Length
    472
  • Mass (Da)
    52,858
  • Last updated
    1991-05-01 v1
  • Checksum
    1D2E49061D12ABF2
MKSILDGLADTTFRTITTDLLYVGSNDIQYEDIKGDMASKLGYFPQKFPLTSFRGSPFQEKMTAGDNPQLVPADQVNITEFYNKSLSSFKENEENIQCGENFMDIECFMVLNPSQQLAIAVLSLTLGTFTVLENLLVLCVILHSRSLRCRPSYHFIGSLAVADLLGSVIFVYSFIDFHVFHRKDSRNVFLFKLGGVTASFTASVGSLFLTAIDRYISIHRPLAYKRIVTRPKAVVAFCLMWTIAIVIAVLPLLGWNCEKLQSVCSDIFPHIDETYLMFWIGVTSVLLLFIVYAYMYILWKAHSHAVRMIQRGTQKSIIIHTSEDGKVQVTRPDQARMDIRLAKTLVLILVVLIICWGPLLAIMVYDVFGKMNKLIKTVFAFCSMLCLLNSTVNPIIYALRSKDLRHAFRSMFPSCEGTAQPLDNSMGDSDCLHKHANNAASVHRAAESCIKSTVKIAKVTMSVSTDTSAEAL

P21554-2

  • Name
    2
  • Synonyms
    CB1a
    , Short
  • Note
    Dubious isoform. A putative downstream initiation AUG is used to produce isoform 2 (PubMed:1718258).
    The use of the first AUG (same as isoform 1) gives a truncated protein of 36 AA.
  • See also
    sequence in UniParc or sequence clusters in UniRef
  • Differences from canonical
    • 1-89: MKSILDGLADTTFRTITTDLLYVGSNDIQYEDIKGDMASKLGYFPQKFPLTSFRGSPFQEKMTAGDNPQLVPADQVNITEFYNKSLSSF → MALQIPPSAPSPLTSCTWAQMTFSTKTS

P21554-3

  • Name
    3
  • Synonyms
    CB1b
  • See also
    sequence in UniParc or sequence clusters in UniRef
  • Differences from canonical

Computationally mapped potential isoform sequences

There are 2 potential isoforms mapped to this entry

View all
EntryEntry nameGene nameLength
F8W908F8W908_HUMANCNR136
F8W187F8W187_HUMANCNR178

Features

Showing features for alternative sequence, sequence conflict.

TypeIDPosition(s)Description
Alternative sequenceVSP_0018681-89in isoform 2
Alternative sequenceVSP_01652922-54in isoform 3
Sequence conflict94in Ref. 12; AAH95513
Sequence conflict103in Ref. 12; AAH95513
Sequence conflict149in Ref. 12; AAH95513
Sequence conflict200in Ref. 5; AAD34320
Sequence conflict216in Ref. 5; AAD34320
Sequence conflict246in Ref. 5; AAD34320
Sequence conflict298in Ref. 12; AAH95513
Sequence conflict332in Ref. 12; AAI00972

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
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

Genome annotation databases

Similar Proteins

Disclaimer

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