Cannabinoid Receptor Type 1 - Mechanism

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. The CB₁ receptor is activated by cannabinoids, generated naturally inside the body (endocannabinoids) or introduced into the body as 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. Functionally, 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 modulated by allosterically synthetic ligands in a positive and negative manner. In vivo exposure to THC impairs long-term potentiation and leads to a reduction of phosphorylated CREB.

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.