Cannabinoid receptor 1

Cannabinoid receptor 1 (CB1), is a G protein-coupled cannabinoid receptor that in humans is encoded by the CNR1 gene. It was discovered by determination and characterization in 1988, and cloned in 1990 for the first time. The human CB1 receptor is expressed in the peripheral nervous system and central nervous system. It is activated by endogenous cannabinoids called endocannabinoids, a group of retrograde neurotransmitters that include lipids, such as anandamide and 2-arachidonoylglycerol; plant phytocannabinoids, such as docosatetraenoylethanolamide found in wild dagga, the compound tetrahydrocannabinol which is an active constituent of the psychoactive drug cannabis; and synthetic analogs of tetrahydrocannabinol. CB1 is antagonized by the phytocannabinoid tetrahydrocannabivarin at low doses and at higher doses, it activates the CB1 receptor as an agonist, but with less potency than tetrahydrocannabinol.

The primary endogenous agonist of the human CB1 receptor is anandamide.

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 A_2A–CB1, CB₁–D2, OX₁–CB₁, μOR–CB_1, 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. Two transcript variants encoding different isoforms have been described for this gene. CNR1 orthologs 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.

The CB1 receptor is a pre-synaptic heteroreceptor that modulates neurotransmitter release when activated in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. The CB1 receptor is activated by cannabinoids, generated naturally inside the body (endocannabinoids) or exogenously, normally through cannabis or a related synthetic compound.

Research suggests that the majority of CB1 receptors are coupled through G_i/o proteins. Upon activation, CB1 receptor exhibits its effects mainly through activation of G_i, which decreases intracellular cAMP concentration by inhibiting its production enzyme, adenylate cyclase, and increases mitogen-activated protein kinase (MAP kinase) concentration. Alternatively, in some rare cases CB1 receptor activation may be coupled to G_s proteins, which stimulate adenylate cyclase. cAMP is known to serve as a second messenger coupled to a variety of ion channels, including the positively influenced inwardly rectifying potassium channels (=Kir or IRK), 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.