Cannabinoid receptor

Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system of vertebrates– a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains. Cannabinoid receptors are activated by three major groups of ligands:

All endocannabinoids and phytocannabinoids are lipophilic.

There are two known subtypes of cannabinoid receptors, termed CB₁ and CB₂. The CB₁ receptor is expressed mainly in the brain (central nervous system or "CNS"), but also in the lungs, liver and kidneys. The CB₂ receptor is expressed mainly in the immune system, in hematopoietic cells, and in parts of the brain.

The protein sequences of CB₁ and CB₂ receptors are about 44% similar. When only the transmembrane regions of the receptors are considered, amino acid similarity between the two receptor subtypes is approximately 68%. In addition, minor variations in each receptor have been identified. Cannabinoids bind reversibly and stereo-selectively to the cannabinoid receptors. Subtype selective cannabinoids have been developed which theoretically may have advantages for treatment of certain diseases such as obesity.

Enzymes involved in biosynthesis/inactivation of endocannabinoids and endocannabinoid signaling in general (involving targets other than CB1/2-type receptors) occur throughout the animal kingdom.

The existence of cannabinoid receptors in the brain was discovered from in vitro studies in the 1980s, with the receptor designated as the cannabinoid receptor type 1 or CB1. The DNA sequence that encodes a G-protein-coupled cannabinoid receptor in the human brain was identified and cloned in 1990. These discoveries led to determination in 1993 of a second brain cannabinoid receptor named cannabinoid receptor type 2 or CB2.

A neurotransmitter for a possible endocannabinoid system in the brain and peripheral nervous system, anandamide (from 'ananda', Sanskrit for 'bliss'), was first characterized in 1992, followed by discovery of other fatty acid neurotransmitters that behave as endogenous cannabinoids having a low-to-high range of efficacy for stimulating CB1 receptors in the brain and CB2 receptors in the periphery.

Cannabinoid receptor type 1 (CB₁) receptors are thought to be one of the most widely expressed G_αi protein-coupled receptors in the brain. One mechanism through which they function is endocannabinoid-mediated depolarization-induced suppression of inhibition, a very common form of retrograde signaling, in which the depolarization of a single neuron induces a reduction in GABA-mediated neurotransmission. Endocannabinoids released from the depolarized post-synaptic neuron bind to CB₁ receptors in the pre-synaptic neuron and cause a reduction in GABA release due to limited presynaptic calcium ions entry.^{[medical citation needed]}