Structure of a cannabinoid receptor and functional expression of the cloned cDNA

Abstract

Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana.

The Psychotomimetic Effects of Intravenous Delta-9-Tetrahydrocannabinol in Healthy Individuals: Implications for Psychosis

“…The psychotropic effects of D-9-THC are mediated by partial agonist effects at CB-1 receptors (CB-1R) where it has modest affinity (K i ¼ 35-80 nmol) and low intrinsic activity (Compton et al, 1992;Gerard et al, 1991;Howlett et al, 2002;Matsuda et al, 1990). However, its hydroxy metabolite has higher affinity and potency.…”

Angiotensin II-induced activation of central AT1 receptors exerts endocannabinoid-mediated gastroprotective effect in rats

“…Cannabinoid receptors are a class of cell membrane receptors under the G proteincoupled receptor (GPCR) superfamily (Matsuda et al, 1990). To date, two cannabinoid receptors have been identified by molecular cloning, CB 1 and CB 2 receptors (Howlett et al, 2002;Matsuda et al, 1990;Munro et al, 1993), however the existence of additional CB receptors have also been proposed (Brown, 2007;Pacher et al, 2005;Ryberg et al, 2007).…”

“…To date, two cannabinoid receptors have been identified by molecular cloning, CB 1 and CB 2 receptors (Howlett et al, 2002;Matsuda et al, 1990;Munro et al, 1993), however the existence of additional CB receptors have also been proposed (Brown, 2007;Pacher et al, 2005;Ryberg et al, 2007). Anandamide is a partial or full agonist of CB 1 receptors, depending on the tissue and biological response measured.…”

(AAT)n repeat in the cannabinoid receptor gene (CNR1): association with cocaine addiction in an African-Caribbean population

“…A longitudinal study of Swedish conscripts 1,2 and other researches point at a possible causal relationship between schizophrenia and the use of cannabis. 3,[4][5][6] As the discovery of Gprotein-coupled seven-transmembrane-domain cannabinoid receptor (CB1) 7 and the cloning of the brain cannabinoid receptor gene (CNR1), 8 more is known about the mechanisms of action of delta-9-tetra hydrocannabinol, the main active ingredient of cannabis. Binding studies have shown that CB1 receptors are abundantly expressed in the brain, especially in limbic and cortical areas (striatum, substantia nigra, nucleus accumbens).…”