News & Events

When

Date - September 1, 2017
1:00 pm - 2:00 pm

What

Marie Foscue Rourk Professor
Department of Chemistry & Biochemistry
University of North Carolina Greensboro

Title: “2-AG Signaling at the Cannaboid CB2 Receptor: A Combined Molecular Dynamics and CB2/Gi Chemical Cross-Linking-Study”

Abstract:

The cannabinoid receptors, CB1 and CB2, are Class A G-protein coupled receptors (GPCRs) that both signal primarily via an inhibitory G-protein, G_i. GPCRs are integral membrane proteins that have seven transmembrane helices (TMHs) arranged to form a closed bundle in the lipid bilayer, with extracellular and intracellular loops that connect the TMH helices, an N-terminus that is extracellular and a C-terminus that is intracellular.  About 40% of all prescription pharmaceuticals on the market today target a GPCR. Examples include Eli Lilly’s Zyprexa, Schering-Plough’s Clarinex, GlaxoSmithKline’s Zantac, and Novartis’s Zelnorm. There is a broad consensus in the pharmaceutical industry that  GPCRs will remain major targets of drug development for the foreseeable future (see http://pubs.acs.org/subscribe/archive/mdd/v07/i11/html/1104feature_filmore .html).

The endogenous ligands identified to activate the CB1 and CB2 receptors, N-arachidonoylethanolamine (AEA) and 2-arachidonoyl glycerol (2-AG), respectively, are both derivatives of the fatty acid, arachidonic acid.  As a result, these ligands are both “lipid-loving”. One long term interest in my lab has been an exploration of lipid pathway entrance of cannabinoid ligands into the cannabinoid receptors and their subsequent activation of G_i protein. To probe this question, we have used microsecond all-atom molecular dynamics to explore (1) the endogenous cannabinoid, 2-AG’s interaction/activation of the cannabinoid CB2 receptor via the lipid bilayer; (2) the subsequent formation of the CB2/G_i signaling complex; and ultimately, (3) CB2 activation of G_i.  This work has been complemented by a comprehensive G protein-coupled receptor-G_i protein chemical cross-linking strategy to map the CB2/G_i interface.  My talk will focus on the results of these simulations and crosslinking experiments and will address why the process of a lipid-derived endogenous ligand activating its cognate GPCR (like 2-AG signaling at CB2) necessarily diverges from the process used by other Class A GPCR sub-families and their water soluble endogenous ligands. [Support: NIDA RO1 DA003934 and KO5 DA021358].