REGULATION OF CANNABINOID RECEPTOR SIGNALING BY RGS (REGULATORS OF G‐PROTEIN SIGNALING) PROTEINS: A NEW PARADIGM FOR MODULATING CB1 AND CB2 RECEPTOR‐MEDIATED SIGNALOSOME

Abstract

CB1 and CB2 cannabinoid receptors belong to Gi protein‐coupled receptor superfamily. RGS proteins are classically known for turning off Gi and Gq‐coupled receptor signaling. CB1 and CB2 cannabinoid receptors are known to elicit a plethora of cellular responses acting through different G‐proteins. However, till date almost nothing is known about RGS‐mediated regulation of cannabinoid receptor signal transduction. In the current study we attempt to define the role of RGS‐proteins in the regulation of CB1 and CB2 receptor signaling in neuronal and endothelial cells respectively.In the current study using real‐time PCR we first screened for native expression of individual RGS proteins in CB1 and CB2 receptor expressing neuronal and endothelial cells lines respectively. Once we found the expression profile of RGS proteins in the specific cell lines we selectively knock down (using SiRNA ) individual RGS proteins in these cell lines. We then measured nitric oxide production following CB1 or CB2 receptor activation in these RGS‐knock down cell lines to determine the specificity of RGS proteins for intercepting CB1 vs. CB2 receptor signaling. Our initial findings showed that a) different RGS proteins are coupled to CB1 and CB receptor signaling and b) RGS proteins can differentially regulate ( inhibit or activate) CB1 and/or CB2 receptor‐mediated nitric oxide production. These results suggest that RGS proteins play a pivotal role in the regulation of cannabinoid receptor signalosomes.