The cannabinoid type-1 receptor carboxyl-terminus, more than just a tail

Abstract

The cannabinoid type-1 (CB1) receptor is a G protein-coupled receptor that binds the main active ingredient of marijuana, Δ9- tetrahydrocannabinol, and has been implicated in several disease states, including drug addiction, anxiety, depression, obesity, and chronic pain. In the two decades since the discovery of CB1, studies at the molecular level have centered on the transmembrane core. This interest has now expanded as we discover that other regions of CB1, including the CB1 carboxyl-terminus, have critical structures that are important for CB 1 activity and regulation. Following the recent description of the three dimensional structure of the full-length CB1 carboxyl-terminal tail [Biopolymers (2009) vol. 91, pp. 565-573], several residues and structural motifs including two α-helices (termed H8 and H9) have been postulated to interact with common G protein-coupled receptor accessory proteins, such as G-proteins and β-arrestins. This discourse will focus on the CB1 carboxyl-terminus; our current understanding of the structural features of this region, evidence for its interaction with proteins, and the impact of structure on the binding and regulatory function of CB1 accessory proteins. The involvement of the carboxyl-terminus in the receptor life cycle including activation, desensitization, and internalization will be highlighted. © 2011 The Authors Journal of Neurochemistry © 2011 International Society for Neurochemistry.