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 proinflammatory 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-AG and anandamide.
Isoform 2:
Only binds 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-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.
Biological Process
Adenylate cyclase-activating G protein-coupled receptor signaling pathway Source: GO_Central
Adenylate cyclase-modulating G protein-coupled receptor signaling pathway Source: UniProtKB
Aging Source: Ensembl
Axonal fasciculation Source: Ensembl
Cannabinoid signaling pathway Source: UniProtKB
Glucose homeostasis Source: Ensembl
G protein-coupled receptor signaling pathway Source: Reactome
G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger Source: ProtInc
Maternal process involved in female pregnancy Source: Ensembl
Memory Source: Ensembl
Negative regulation of action potential Source: Ensembl
Negative regulation of blood pressure Source: Ensembl
Negative regulation of dopamine secretion Source: Ensembl
Negative regulation of fatty acid beta-oxidation Source: Ensembl
Negative regulation of mast cell activation Source: Ensembl
Negative regulation of nitric-oxide synthase activity Source: Ensembl
Negative regulation of serotonin secretion Source: Ensembl
Positive regulation of acute inflammatory response to antigenic stimulus Source: Ensembl
Positive regulation of apoptotic process Source: Ensembl
Positive regulation of blood pressure Source: Ensembl
Positive regulation of fever generation Source: Ensembl
Positive regulation of neuron projection development Source: Ensembl
Regulation of feeding behavior Source: Ensembl
Regulation of insulin secretion Source: Ensembl
Regulation of metabolic process Source: GO_Central
Regulation of penile erection Source: Ensembl
Regulation of synaptic transmission, GABAergic Source: Ensembl
Regulation of synaptic transmission, glutamatergic Source: Ensembl
Response to cocaine Source: Ensembl
Response to ethanol Source: Ensembl
Response to lipopolysaccharide Source: Ensembl
Response to morphine Source: Ensembl
Response to nicotine Source: Ensembl
Response to nutrient Source: Ensembl
Retrograde trans-synaptic signaling by endocannabinoid Source: Ensembl
Sensory perception of pain Source: Ensembl
Spermatogenesis Source: Ensembl
Trans-synaptic signaling by endocannabinoid, modulating synaptic transmission Source: Ensembl
Cellular Location
Cell membrane; Mitochondrion outer membrane; Membrane raft; Axon; Presynapse. 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).
Involvement in disease
Obesity (OBESITY):
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. 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.
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