Cannabinoid receptor constitutive activity

Nie, J., and Lewis, D. L. (2001). Structural domains of the GB1 cannabinoid receptor that contribute to constitutive activity and G-protein sequestration. /. Neurosci. 21, 8758-8764. 

There are specific binding sites for cannabinoids, whose endogenous antagonists belong to the class of endocannabinoids. The human organism produces endocan-nabinoids from long-chain polyunsaturated fatty acids, they bind to cannabinoid (CB) receptors and activate them. The CB receptors and endocannabinoids constitute the endocannabinoid system [31]. THC binds to both types of receptors CB1 and CB2. The absence of cannabinoid receptors in the brain stem, the seat of the centers of respiration and other vital functions, explains the low toxicity of cannabinoids. 

Clearly there is now incontrovertible evidence for the existence of a mammalian endocannabinoid system that consists of at least two types of cannabinoid receptor, CBi and CB2, and of endogenous agonists (endocannabinoids) for these receptors. Agonists that activate both these receptor types with similar potency or that show marked selectivity for one or other receptor type have been discovered, as have potent CBi- and CB2-selective cannabinoid receptor antagonists. Quantitative and sensitive in vitro and in vivo bioassays for these ligands are also available, and these have played a crucial role in determining the CBi and CB2 receptor affinities and intrinsic activities of a number of cannabinoids. There is good evidence that the endocannabinoid system can become Ionically active and that this is due in some instances to endocannabinoid release and in other instances to the ability of cannabinoid receptors to exist in a constitutively activity state, not only when over-... 

Savinainen JR, Saario SM, Niemi R, jarvinen T, Laitinen JT (2003) An optimized approach to study endocannabinoid signaling evidence against constitutive activity of rat brain adenosine Al and cannabinoid CBI receptors. Br J Pharmacol 140 1451-1459... 

Abadji V, Lucas-Lenard JM, Chin C, Kendall DA (1999) Involvement of the carboxyl terminus of the third intracellular loop of the cannabinoid CB 1 receptor in constitutive activation of Gs. J Neurochem 72 2032-2038... 

Early studies of forskohn-stimulated cAMP in mouse brain synaptosomes showed biphasic responses to A -THC and A -THC (Little and Martin, 1991). Some cannabinoids did not alter cAMP levels. These early studies suggesting biphasic effects of cannabinoids have been confirmed, both in brain and in CB,-receptor-transfected cells (Glass and Felder, 1997 Bonhaus et al., 1998). Emthermore, a mutational study points to selective G-protein activation as a possible mechanism for the biphasic effects of cannabinoids, because a point mutation produced a constitutively active CB, receptor that coupled to G instead of G, (Abadji et al., 1999). AEA is a partial agonist in activation of this stimulatory pathway (Bonhaus et al., 1998). 2-arachidonylglycerol has not been examined for stimulatory effects. 

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