Cannabinoid receptor 1

The CB1 receptor shares the structure characteristic of all G-protein-coupled receptors, possessing seven transmembrane domains connected by three extracellular and three intracellular loops, an extracellular N-terminal tail, and an intracellular C-terminal tail. The receptor may exist as a homodimer or form heterodimers or other GPCR oligomers with different classes of G-protein-coupled receptors. Observed heterodimers include A2A–CB1, CB1–D2, OX1–CB1, μOR–CB1, while many more may only be stable enough to exist in vivo. The CB1 receptor possesses an allosteric modulatory binding site. The CB1 receptor is encoded by the gene CNR1, located on human chromosome 6. have been identified in most mammals. The CNR1 gene has a structure consisting of a single coding-exon and multiple alternative 5' untranslated exons. The CB1 receptor is created by transcription of the last exon on the CNR1 gene. ==Mechanism==

The CB1 receptor is a pre-synaptic heteroreceptor that modulates neurotransmitter release when activated in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. and calcium channels, which are activated by cAMP-dependent interaction with such molecules as protein kinase A (PKA), protein kinase C (PKC), Raf-1, ERK, JNK, p38, c-fos, c-jun, and others. In terms of function, the inhibition of intracellular cAMP expression shortens the duration of pre-synaptic action potentials by prolonging the rectifying potassium A-type currents, which is normally inactivated upon phosphorylation by PKA. This inhibition grows more pronounced when considered with the effect of activated CB1 receptors to limit calcium entry into the cell, which does not occur through cAMP but by a direct G-protein-mediated inhibition. As presynaptic calcium entry is a requirement for vesicle release, this function will decrease the transmitter that enters the synapse upon release. The relative contribution of each of these two inhibitory mechanisms depends on the variance of ion channel expression by cell type. The CB1 receptor can also be allosterically modulated by synthetic ligands in a positive and negative manner. In vivo exposure to tetrahydrocannabinol impairs long-term potentiation and leads to a reduction of phosphorylated CREB. The signaling properties of activated CB1 are furthermore modified by the presence of SGIP1, that hinders receptor internalization and decreases ERK1/2 signalling while augmenting the interaction with GRK3, β-arrestin-2. In summary, CB1 receptor activity has been found to be coupled to certain ion channels, in the following manner: • Positively to inwardly rectifying and A-type outward potassium channels. • Negatively to D-type outward potassium channels • Negatively to N-type and P/Q-type calcium channels. ==Expression==

CB1 receptors are localized throughout the central and peripheral nervous systems, particularly on axon terminals in the cerebellum, hippocampus, basal ganglia, frontal cortex, amygdala, hypothalamus, and midbrain. Acting as a neuromodulator, the CB1 receptor inhibits the release of both excitatory and inhibitory neurotransmitters including acetylcholine, glutamate, GABA, noradrenaline, 5-HT, dopamine, D-aspartate, and cholecystokinin. Brain The CB1 receptor is recognized as the most abundant metabotropic receptor in the brain. This means that, although synaptic strength/frequency, and thus potential to induce LTP, is lowered, net hippocampal activity is raised. In addition, CB1 receptors in the hippocampus indirectly inhibit the release of acetylcholine. This serves as the modulatory axis opposing GABA, decreasing neurotransmitter release. Cannabinoids also likely play an important role in the development of memory through their neonatal promotion of myelin formation, and thus the individual segregation of axons. Basal ganglia CB1 receptors are expressed throughout the basal ganglia and have well-established effects on movement in rodents. As in the hippocampus, these receptors inhibit the release of glutamate or GABA transmitter, resulting in decreased excitation or reduced inhibition based on the cell they are expressed in. Consistent with the variable expression of both excitatory glutamate and inhibitory GABA interneurons in both the basal ganglia's direct and indirect motor loops, synthetic cannabinoids are known to influence this system in a dose-dependent triphasic pattern. Decreased locomotor activity is seen at both higher and lower concentrations of applied cannabinoids, whereas an enhancement of movement may occur upon moderate dosages. In the visual system, cannabinoids agonist induce a dose dependent modulation of calcium, chloride and potassium channels. This alters vertical transmission between photoreceptor, bipolar and ganglion cells. Altering vertical transmission in turn results in the way vision is perceived. == Physiological and pathological conditions ==

The activation of CB1 in the human body generally inhibits neurotransmitter release, controls pain, regulates metabolism, and monitors the cardiovascular system. CB1 receptors are implicated in a number of physiological processes related to the central nervous system (CNS) including brain development, learning and memory, motor behavior, regulation of appetite, body temperature, pain perception, and inflammation. In several brain regions, including the dorsolateral prefrontal cortex (DLPFC) and hippocampus, dysregulation of the CB1 receptor is implicated in the development of schizophrenia. Abnormal functioning of the CB1 receptor compromises intricate neural systems that are responsible for controlling cognition and memory, which contributes to the pathology. PET imaging modalities implicate that alterations of CB1 levels in certain brain systems are strongly associated with schizophrenia symptoms. Neurobehavioral disorders, such as attention deficit hyperactivity disorder (ADHD), are associated with genetic variants of CNR1 in rat models of ADHD. ==Use of antagonists==

Selective CB1 agonists may be used to isolate the effects of the receptor from the CB2 receptor, as most cannabinoids and endocannabinoids bind to both receptor types. --> == Ligands ==

Agonists • Minocycline • Dronabinol • AM404 Selective • Epigallocatechin • Epicatechin • Kavain • Yangonin • Oleamide Unspecified efficacy • N-Arachidonoyl dopamine • Cannabinol • HU-210 • 11-Hydroxy-THC • Levonantradol Partial Endogenous • 2-Arachidonyl glyceryl ether Phyto • Tetrahydrocannabinol • Hexahydrocannabinol Full Endogenous • 2-Arachidonoylglycerol Synthetic • JWH-073 • AM-2201 • CP 55,940 • JWH-018 • WIN 55,212-2 Allosteric agonist • GAT228 Antagonists • Cannabigerol • Ibipinabant • Otenabant • Tetrahydrocannabivarin • Virodhamine (Endogenous CB1 antagonist and CB2 agonist) Inverse agonists • Rimonabant • Taranabant • Zevaquenabant • Monlunabant • INV-202 Allosteric modulators • Lipoxin A4 – endogenous, PAM • ZCZ-011 – PAM • Pregnenolone – endogenous, NAM • Cannabidiol – NAM • Fenofibrate – NAM • GAT100 – NAM • PSNCBAM-1 – NAM • RVD-Hpα – NAM ==Binding affinities==

The CNR1 gene is used in animals as a nuclear DNA phylogenetic marker. and contributed to reveal that placental orders are distributed into five major clades: Xenarthra, Afrotheria, Laurasiatheria, Euarchonta, and Glires. CNR1 has also proven useful at lower taxonomic levels, such as rodents, and for the identification of dermopterans as the closest primate relatives. === Paralogues === Source: • CNR2 • S1PR1 • LPAR1 • S1PR3 • S1PR5 • S1PR2 • GPR6 • GPR12 • S1PR4 • LPAR3 • LPAR2 • GPR3 • MC3R • MC5R • MC2R • MC1R • MC4R • GPR119 == See also ==