Recombinant Mouse Cannabinoid receptor 1 (Cnr1)-VLPs Protein

Function

G protein-coupled receptor for cannabinoids, including endocannabinoids (eCBs), such as N-arachidonoylethanolamide (also called anandamide or AEA) and 2-arachidonoylglycerol (2-AG) (PubMed:22388959, PubMed:9888857). Mediates many cannabinoid-induced effects, acting, among others, on food intake, memory loss, gastrointestinal motility, catalepsy, ambulatory activity, anxiety, chronic pain (PubMed:27828947, PubMed:9888857). Signaling typically involves reduction in cyclic AMP (PubMed:27828947, PubMed:8832654). 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 Ca(2+) channels in a constitutive, as well as agonist-dependent manner (By similarity). In cerebral vascular smooth muscle cells, cannabinoid-induced inhibition of voltage-gated Ca(2+) 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 pro-inflammatory 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)

Subcellular Location

Cell membrane (Multi-pass membrane protein); Mitochondrion outer membrane; Cell projection, axon; Presynapse

Disease Association

[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)]

Tissue Specificity

Expressed in brain neurons (at protein level) (PubMed:22388959). Detected throughout the striatum, cortex and hippocampus, with highest levels in the lateral striatum (PubMed:10891614, PubMed:15606779, 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:25707796, PubMed:25869131). 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)

Subunit

Interacts (via C-terminus) with CNRIP1 (By similarity). Associates with G protein alpha subunits, including G(i) alpha-1/GNAI1, G(i) alpha-2/GNAI2, G(i) alpha-3/GNAI3 and G(o)-alpha/GNAO1; palmitoylation is important for interaction with GNAI3 and GNAO1 (PubMed:27828947)

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