Alternative titles; symbols
HGNC Approved Gene Symbol: CNR1
Cytogenetic location: 6q15 Genomic coordinates (GRCh38): 6:88,139,864-88,167,349 (from NCBI)
Cannabinoids are psychoactive ingredients of marijuana, principally delta-9-tetrahydrocannabinol (THC), as well as the synthetic analogs. Matsuda et al. (1990) cloned a cannabinoid receptor from a rat brain.
Gerard et al. (1991) isolated a cDNA encoding a cannabinoid receptor from a human brainstem cDNA library. The deduced amino acid sequence encoded a protein of 472 residues which shared 97.3% identity with the rat cannabinoid receptor cloned by Matsuda et al. (1990). They provided evidence for the existence of an identical cannabinoid receptor expressed in human testis.
Oleylethanolamide (OEA) is a natural analog of the endogenous cannabinoid anandamide. Like anandamide, OEA is produced in cells in a stimulus-dependent manner and is rapidly eliminated by enzymatic hydrolysis, suggesting a function in cellular signaling. However, OEA does not activate cannabinoid receptors. Rodriguez de Fonseca et al. (2001) demonstrated in rats that food deprivation markedly reduces OEA biosynthesis in the small intestine. Administration of OEA caused a potent and persistent decrease in food intake and gain in body mass. This anorexic effect is behaviorally selective and is associated with the discrete activation of brain regions (the paraventricular hypothalamic nucleus and the nucleus of the solitary tract) involved in the control of satiety. OEA did not affect food intake when injected into the brain ventricles, and its anorexic actions were prevented when peripheral sensory fibers were removed by treatment with capsaicin. Rodriguez de Fonseca et al. (2001) concluded that OEA is a lipid mediator involved in the peripheral regulation of feeding.
Hohmann et al. (2005) demonstrated that an opioid-independent form of stress-induced analgesia is mediated by the release of endogenous marijuana-like compounds in rat brain. Blockade of cannabinoid CB1 receptors in the periaqueductal gray matter of the midbrain prevented nonopioid stress-induced analgesia. In this region, stress elicits the rapid formation of 2 endogenous cannabinoids, the lipids 2-arachidonoylglycerol and anandamide. An inhibitor of the 2-arachidonoylglycerol deactivating enzyme, monoacylglycerol lipase, selectively increased 2-arachidonoylglycerol concentrations and, when injected into the periaqueductal gray matter, enhanced stress-induced analgesia in a CB1-dependent manner. Inhibitors of the anandamide-deactivating enzyme fatty-acid amide hydrolase (FAAH; 602935), which selectively elevate anandamide concentrations, exerted similar effects. Hohmann et al. (2005) concluded that the coordinated release of 2-arachidonoylglycerol and anandamide in the periaqueductal gray matter might mediate opioid-independent stress-induced analgesia.
Berghuis et al. (2005) found that anandamide acted as a chemoattractant and regulated rat Cb1r-positive interneuron migration by activating Trkb (NTRK2; 600456). Anandamide-induced chemotaxis was additive with Bdnf (113505)-induced interneuron migration, but prolonged anandamide exposure antagonized Bdnf-induced differentiation of cortical interneurons. Neuronal differentiation was associated with simultaneous recruitment of Cb1r and Trkb to axon terminal segments in Cb1r-positive interneurons, and endocannabinoids induced the assembly of Cb1r/Trkb complexes. In utero exposure of pups to cannabinoids found in marijuana increased the density of hippocampal Cck (118440)-positive interneurons, suggesting that overactivation of CB1Rs affects postnatal positioning of developing neurons and prevents proper patterning of cortical neuronal networks.
In mouse hippocampal and amygdala slices, Chevaleyre et al. (2007) found that Rim1-alpha (RIMS1; 606629) is a key mediator of CNR1-mediated suppression of neurotransmitter release at presynaptic synapses. Studies manipulating cAMP and protein kinase A (PRKAR1A; 188830) levels showed that the presynaptic cAMP/PKA pathway is required for downstream activation of Cnr1-induced long-term, but not short-term, plasticity. Brief activation of Cnr1 leads to short-term depression by blocking presynaptic voltage-gated calcium channels or altered G-protein signaling, resulting in a transient effect. In contrast, long-term depression triggers a PKA and Rim1-dependent modification in the release machinery. The overall findings demonstrated that short and long-term presynaptic plasticity at inhibitory synapses in these brain regions work via different pathways, and that Rim1-alpha is a mediator of long-term plasticity.
By yeast 2-hybrid screening of a human brain cDNA library to identify CB1 receptor-interacting proteins, Niehaus et al. (2007) identified CRIP1 (CNRIP1; 618538). Deletion analysis showed that the distal C-terminal region of rat CB1 receptor interacted with amino acids 34 to 110 of rat Crip1. Coexpression analysis revealed that both rat Crip1 isoforms, Crip1a and Crip1b, colocalized with CB1 receptor near the plasma membrane in rat superior cervical ganglion (SCG) neurons. Crip1a, but not Crip1b, suppressed tonic inhibition of voltage-gated Ca(2+) channels by CB1 receptors. However, neither Crip1a nor Crip1b altered expression or affinity of CB1 receptor, the time course of Ca(2+) current inhibition, or recovery from inhibition by CB1 receptor agonist in SCG neurons.
To understand the logic underlying decision making in the signaling network controlling CB1R-induced neurite outgrowth, Bromberg et al. (2008) profiled the activation of several hundred transcription factors after cell stimulation. They assembled an in silico signaling network by connecting CB1R to 23 activated transcription factors. Statistical analysis of this network predicted a role for the breast cancer-1 protein BRCA1 (113705) in neuronal differentiation and a new pathway from CB1R through phosphoinositol 3-kinase (see 601232) to the transcription factor PAX6 (607108). Both predictions were experimentally confirmed. Results of transcription factor activation experiments that used pharmacologic inhibitors of kinases revealed a network organization of partial OR gates regulating kinases stacked above AND gates that control transcription factors, which together allowed for distributed decision making in CB1R-induced neurite outgrowth.
Pernia-Andrade et al. (2009) found that endocannabinoids, produced upon strong nociceptive stimulation, activated type 1 cannabinoid (CB1) receptors on inhibitory dorsal horn neurons to reduce the synaptic release of GABA and glycine and thus rendered nociceptive neurons excitable by nonpainful stimuli. Pernia-Andrade et al. (2009) concluded that spinal endocannabinoids and CB1 receptors on inhibitory dorsal horn interneurons act as mediators of heterosynaptic pain sensitization and play an unexpected role in dorsal horn pain-controlling circuits.
Benedetti et al. (2011) found that the CB1 receptor mediated nonopioid placebo analgesia in humans. Individuals given the CB1 receptor antagonist rimonabant reported complete block of the pain-relieving placebo response after preconditioning with the nonopioid ketorolac, whereas no change in pain relief was observed in those preconditioned with the opioid morphine. The findings implicated the endocannabinoid system in placebo analgesia when the opioid system is not involved.
Koch et al. (2015) tested whether CB1R-controlled feeding in sated mice is paralleled by decreased activity of proopiomelanocortin (POMC; 176830) neurons. They showed that chemical promotion of CB1R activity increases feeding, and, notably, CB1R activation also promoted neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for CB1R-induced feeding, since 'designer receptors exclusively activated by designer drugs' (DREADD)-mediated inhibition of POMC neurons diminished CB1R-driven feeding, whereas DREADD-mediated activation of POMC neurons enhanced it. The POMC gene encodes both the anorexigenic peptide alpha-MSH and the opioid peptide beta-endorphin. CB1R activation selectively increases beta-endorphin but not alpha-MSH release in hypothalamus, and systemic or hypothalamic administration of the opioid receptor antagonist naloxone blocks acute CB1R-induced feeding. These processes involve mitochondrial adaptations that, when blocked, abolish CB1R-induced cellular responses and feeding. Koch et al. (2015) concluded that these results uncovered a previously unsuspected role of POMC neurons in the promotion of feeding by cannabinoids.
Hebert-Chatelain et al. (2016) showed that acute cannabinoid-induced memory impairment in mice requires activation of hippocampal mitochondrial CB1 (mtCB1) receptors. Genetic exclusion of CB1 receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission, and memory formation. mtCB1 receptors signal through intramitochondrial G-alpha-i (see 139310) protein activation and consequent inhibition of soluble adenylyl cyclase (SAC; 605205). The resulting inhibition of protein kinase A (PKA; see 188830)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system eventually leads to decreased cellular respiration. Hippocampal inhibition of SAC activity or manipulation of intramitochondrial PKA signaling or phosphorylation of the complex I subunit NDUFS2 (602985) inhibit bioenergetic and amnesic effects of cannabinoids. Thus, Hebert-Chatelain et al. (2016) concluded that the G protein-coupled mtCB1 receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to memory formation, these data revealed that bioenergetic processes are primary acute regulators of cognitive functions.
Guggenhuber et al. (2016) found that overexpression of Cnrip1a in mouse hippocampus increased CB1 receptor activity by enhancing cannabinoid-induced G protein activation. Cnrip1a overexpression did not affect basal CB1 receptor-mediated short-term plasticity, but it prolonged agonist-induced CB1 receptor signaling. Cnrip1a overexpression in hippocampal neurons of mice diminished the severity of acute epileptiform seizures broadly, without affecting emotional and motor behavior.
Jimenez-Blasco et al. (2020) showed that activation of mouse astroglial CB1 receptors associated with mitochondrial membranes (mtCB1) hampers the metabolism of glucose and the production of lactate in the brain, resulting in altered neuronal functions and, in turn, impaired behavioral responses in social interaction assays. Specifically, activation of astroglial mtCB1 receptors reduces the phosphorylation of the mitochondrial complex I subunit NDUFS4 (602694), which decreases the stability and activity of complex I. This leads to a reduction in the generation of reactive oxygen species by astrocytes and affects the glycolytic production of lactate through the HIF1 (see 603348) pathway, eventually resulting in neuronal redox stress and impairment of behavioral responses in social interaction assays. Genetic and pharmacologic correction of each of these effects abolishes the effect of cannabinoid treatment on the observed behavior. Jimenez-Blasco et al. (2020) concluded that their findings suggested that mtCB1 receptor signaling can directly regulate astroglial glucose metabolism to fine-tune neuronal activity and behavior in mice.
Crystal Structure
Shao et al. (2016) reported the use of G protein-coupled receptor (GPCR) engineering and lipidic cubic phase crystallization to determine the structure of the human CB1 receptor bound to the inhibitor taranabant at 2.6-angstrom resolution. Shao et al. (2016) found that the extracellular surface of CB1, including the highly conserved membrane-proximal N-terminal region, is distinct from other lipid-activated GPCRs, forming a critical part of the ligand-binding pocket. Docking studies further demonstrated how this same pocket may accommodate the cannabinoid agonist THC.
Hoehe et al. (1991) determined the genomic localization of the CNR1 gene by combination of genetic linkage mapping and chromosomal in situ hybridization. Close linkage was suggested with CGA (118850), which is located at 6q21.1-q23; maximum lod = 2.71 at theta = 0.0. Moreover, CNR1 was linked to markers that define locus D6Z1, a sequence localized exclusively to centromeres of all chromosomes and enriched on chromosome 6.
Using a cosmid clone of the entire coding sequence of the human gene, Modi and Bonner (1991) mapped the human CNR1 locus to 6q14-q15 by in situ hybridization.
Russo et al. (2007) investigated whether SNPs of the CNR1 gene are associated with body fat mass and distribution in 2 independent samples of white European adult men. They genotyped the 3813A/G and 4895A/G SNPs in the exon 4 of CNR1 in 930 participants to the Olivetti Prospective Heart Study in southern Italy and in 216 participants to the Wandsworth Heart and Stroke Study in the United Kingdom. The 3813G allele was associated with increased subscapular skinfold thickness (24.2 + 9.1 vs 22.8 + 7.7 mm; p = 0.031) and waist circumference (99.1 + 8.8 vs 97.7 + 8.8 cm; p = 0.050). Russo et al. (2007) concluded that genetic variants of CNR1 are associated with obesity-related phenotypes in men.
Ledent et al. (1999) investigated the function of the central cannabinoid receptor (CB1) by disrupting the gene in mice. Mutant mice did not respond to cannabinoid drugs, demonstrating the exclusive role of CB1 in mediating analgesia, reinforcement, hypothermia, hypolocomotion, and hypotension. The acute effects of opiates were unaffected, but the reinforcing properties of morphine and the severity of the withdrawal syndrome were strongly reduced. These observations suggested that CB1 is involved in the motivational properties of opiates and in the development of physical dependence, and extended the concept of an interconnected role of CB1 and opiate receptors in the brain areas mediating addictive behavior.
Di Marzo et al. (2001) showed that following temporary food restriction, CB1 receptor knockout mice eat less than their wildtype littermates, and the CB1 antagonist SR141716A reduces food intake in wildtype but not knockout mice. Furthermore, defective leptin (164160) signaling is associated with elevated hypothalamic, but not cerebellar, levels of endocannabinoids in obese db/db and ob/ob mice and Zucker rats. Acute leptin treatment of normal rats and ob/ob mice reduces anandamide and 2-arachidonoyl glycerol in the hypothalamus. Di Marzo et al. (2001) concluded that endocannabinoids in the hypothalamus may tonically activate CB1 receptors to maintain food intake and form part of the neural circuitry regulated by leptin.
2-Arachidonoyl glycerol (2-AG) is an endogenous cannabinoid that binds to CNR1. Panikashvili et al. (2001) demonstrated that after injury to the mouse brain, 2-AG may have a neuroprotective role in which the cannabinoid system is involved. After closed head injury in mice, the level of endogenous 2-AG was significantly elevated. Administration of synthetic 2-AG to mice after closed head injury resulted in significant reduction of brain edema, better clinical recovery, reduced infarct volume, and reduced hippocampal cell death compared with controls. The beneficial effect of 2-AG was dose-dependently attenuated by an antagonist of CNR1.
Acquisition and storage of aversive memories is one of the basic principles of central nervous systems throughout the animal kingdom. In the absence of reinforcement, the resulting behavioral response will gradually diminish to be finally extinct. The cannabinoid receptor-1 and endocannabinoids are present in memory-related brain areas and modulate memory. Marsicano et al. (2002) demonstrated that the endogenous cannabinoid system has a central function in extinction of aversive memories. CB1-deficient mice showed strongly impaired short-term and long-term extinction in auditory fear-conditioning tests, with unaffected memory acquisition and consolidation. Treatment of wildtype mice with a CB1 antagonist mimicked the phenotype of CB1-deficient mice, revealing that CB1 is required at the moment of memory extinction. Consistently, tone presentation during extinction trials resulted in elevated levels of endocannabinoids in the basolateral amygdala complex, a region known to control extinction of aversive memories. In the basolateral amygdala, endocannabinoids and CB1 were crucially involved in long-term depression of GABA-mediated inhibitory currents. Marsicano et al. (2002) proposed that endocannabinoids facilitate extinction of aversive memories through their selective inhibitory effects on local inhibitory networks in the amygdala.
Marsicano et al. (2003) generated conditional mutant mice that lacked expression of the cannabinoid receptor type 1 in principal forebrain neurons but not in adjacent inhibitory interneurons. In mutant mice, the excitotoxin kainic acid induced excessive seizures in vivo. The threshold to kainic acid-induced neuronal excitation in vitro was severely reduced in hippocampal pyramidal neurons of mutants. Kainic acid administration rapidly raised hippocampal levels of anandamide and induced protective mechanisms in wildtype principal hippocampal neurons. These protective mechanisms could not be triggered in mutant mice. Marsicano et al. (2003) concluded that the endogenous cannabinoid system provides an on-demand protection against acute excitotoxicity in central nervous system neurons.
In mice, Wang et al. (2004) found that genetic or pharmacologic silencing of CB1 caused retention of a large number of embryos in the oviduct, leading to pregnancy failure. Pharmacologic manipulation of cannabinoid and adrenergic signaling resulted in changes in smooth muscle contraction in the oviduct which impeded embryo transport. Wang et al. (2004) concluded that CB1 and beta-2-adrenergic receptors (ADRB2; 109690) in the oviduct muscularis act together in moving the embryo along the fallopian tube into the uterus, and noted that disruption of this pathway may play a role in ectopic pregnancy.
Idris et al. (2005) demonstrated that Cb1-null mice had increased bone mass and were protected from ovariectomy-induced bone loss. Pharmacologic antagonists of CB1 and CB2 (605051) receptors prevented ovariectomy-induced bone loss in vivo and caused osteoclast inhibition in vitro by promoting osteoclast apoptosis and inhibiting production of several osteoclast survival factors. Idris et al. (2005) concluded that the CB1 receptor has a role in the regulation of bone mass and ovariectomy-induced bone loss.
Berghuis et al. (2007) reported that CB1 cannabinoid receptors are enriched in the axonal growth cones of GABAergic interneurons in the rodent cortex during late gestation. Endocannabinoids triggered CB1R internalization and elimination from filopodia and induced chemorepulsion and collapse of axonal growth cones of these GABAergic interneurons by activating RhoA (165390). Similarly, endocannabinoids diminished the galvanotropism of Xenopus laevis spinal neurons. Berghuis et al. (2007) concluded that their findings, together with the impaired target selection of cortical GABAergic interneurons lacking CB1Rs, identified endocannabinoids as axon guidance cues and demonstrated that endocannabinoid signaling regulates synaptogenesis and target selection in vivo.
In an animal model for cutaneous contact hypersensitivity, Karsak et al. (2007) found that mice lacking both known cannabinoid receptors displayed exacerbated allergic inflammation. In contrast, fatty acid amide hydrolase (FAAH; 602935)-deficient mice, which have increased levels of endocannabinoid anandamide, displayed reduced allergic responses in the skin. Cannabinoid receptor antagonists exacerbated allergic inflammation, whereas receptor agonists attenuated inflammation. Karsak et al. (2007) concluded that their results demonstrated a protective role of the endocannabinoid system in contact allergy in the skin and suggested a target for therapeutic intervention.
Monory et al. (2007) conditionally deleted Cb1 in specific neuronal subpopulations in mice to dissect the neuronal circuits involved in the effects of THC. Deletion of Cb1 in principal neurons abolished or strongly reduced the behavioral and autonomic responses to THC. Deletion of Cb1 in cortical glutamatergic neurons reduced the locomotor and hypothermic effects of THC. Deletion of Cb1 from the majority of striatal neurons and a subpopulation of cortical glutamatergic neurons blocked the cataleptic effect of THC. Responses to THC in mice lacking Cb1 in GABAergic neurons were similar to those in wildtype mice in all tests conducted. Monory et al. (2007) concluded that the pharmacologic actions of THC depend on expression of CB1 in several neuronal populations, but not in GABAergic interneurons.
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