1. Biochem Pharmacol. 2010 Jul 1;80(1):1-12. Epub 2010 Mar 3.

Functionally selective cannabinoid receptor signalling: therapeutic implications 
and opportunities.

Bosier B, Muccioli GG, Hermans E, Lambert DM.

Unité de Chimie Pharmaceutique et de Radiopharmacie (CMFA 7340), Louvain Drug
Research Institute, Brussels, Belgium.

The CB(1) and CB(2) cannabinoid receptors are G protein-coupled receptors (GPCRs)
recognized by a variety of endogenous ligands and activating multiple signalling 
pathways. This multiplicity of ligands and intracellular transduction mechanisms 
supports a complex control of physiological functions by the endocannabinoid
system, but requires a finely tuned regulation of the signalling events triggered
on receptor activation. Here we review the diverse signalling pathways activated 
by the cannabinoid receptors and discuss the mechanisms allowing for specificity 
in the associated functional responses triggered by endogenous or exogenous
ligands. At variance with the classical concept that all agonists at a given GPCR
induce a similar repertoire of downstream events in all tissues, we also
summarize the experimental evidence supporting the existence of functional
selectivity and protean agonism at cannabinoid receptors. By placing emphasis on 
the ligand- or constitutive activity-dependent specifications of receptor-G
protein coupling, these concepts explain how distinct cannabinoid ligands may
activate specific downstream mediators. Finally, although both the diversity and 
specificity in cannabinoid signalling are now established in vitro, few data are 
available from in vivo studies. Therefore, we conclude this review by examining
the experimental evidence supporting the physiological relevance of this
complexity in the cannabinoid system. The ability to selectively manipulate
physiological functions, through activation of defined signalling cascades, will 
in all likelihood help in the development of efficacious and safe
cannabinoid-based therapeutics for a variety of indications. (c) 2010 Elsevier
Inc. All rights reserved.

PMID: 20206137 [PubMed - indexed for MEDLINE]