Hot topic: GPR3 and GPR6, novel molecular targets for cannabidiol

Cannabidiol is a major metabolite from the Cannabis plant, although levels vary dependent on genetic, regional, cultivation and other factors.  It lacks the psychotropic nature of THC, but has been reported to have many biological effects, to the extent that clinical trials for infantile intractable epilepsy are currently ongoing in the US. GPR3 and GPR6 are orphan GPCRs, which have previously been reported to elevate cAMP levels constitutively when expressed in recombinant systems.  Although there was some evidence for activation by sphingosine 1-phosphate, this was not reproduced.  In this report, a number of endogenous and Cannabis-derived metabolites were examined for their effects on β-arrestin2 recruitment in cells expressing either GPR3 or GPR6.  Of these agents, only CBD caused a reduction in β-arrestin2 recruitment in a concentration-dependent manner, with pIC50 values of 5.9 and 6.7 at GPR3 and GPR6, respectively.  The authors suggest that the inverse agonist nature of CBD at these receptors might be of relevance for neurodegenerative disorders, such as Parkinson’s and Alzheimer’s Disease.

Comments by Steve Alexander (@mqzspa)

(1) Laun AS, Song ZH. (2017) GPR3 and GPR6, novel molecular targets for cannabidiol. Biochem Biophys Res Commun. 2017 May 29. pii: S0006-291X(17)31074-4. doi: 10.1016/j.bbrc.2017.05.165. [Epub ahead of print] [PMID:28571738]