Role of Lipid Rafts and the Underlying Filamentous-Actin Cytoskeleton in Cannabinoid Receptor 1 Signaling

Abstract

The cannabinoid 1 receptor, CB1, has evolved as a major regulatory molecule for almost all known aspects of the development and function of the central nervous system (CNS), with biological actions ranging from proper CNS cellularity to complex behaviors such as fear, appetite, and addiction. It is therefore critical to understand the mechanisms and intracellular signal transduction pathways that CB1 utilizes for its acute and long-term actions, in particular activation of the major effector extracellular signal-regulated kinase (ERK) in discrete amplification waves. This highly complex regulation of CB1 signaling to ERK is facilitated by specialized membrane microdomains, the lipid rafts. Integral components of rafts are required for proper CB1 presentation at the plasma membrane as shown by confocal analysis, while the dynamic and hierarchic activation of its major proximal effectors protein kinase Cε, Src, and Fyn requires raft integrity, additionally causing fibroblast growth factor receptor transactivation. Thus, lipid rafts constitute the plasma membrane platform on which CB1 signaling is initiated and organized. © 2016 Elsevier Inc. All rights reserved.