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

Abstract

J. Neurochem. (2011) 117, 1–18. 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 CB1 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.

A Membrane-proximal, C-terminal α-Helix Is Required for Plasma Membrane Localization and Function of the G Protein-coupled Receptor (GPCR) TGR5

“…Similar findings have been described for the human cannabinoid receptor 1 (27,55,56). Using overexpression, purification, and circular dichroism spectroscopy analysis of the fulllength CB1 C terminus as well as different substitution variants, it was demonstrated that it is the level of hydrophobicity rather than specific amino acids that is critical for helix formation and, thus, targeting to the PM of this GPCR (27,55,56). Another example that hydrophobic amino acid residues in the membrane-proximal C terminus allowing ␣-helix formation are essential for ER exit and PM localization has been described for the human vasopressin II receptor (28).…”

“…Taken together our results suggest that the FX 6 LL motif itself has an important role for ␣-helix formation but not as a sequence-specific sorting motif in the TGR5␤ 2 AR chimera. Similar findings have been described for the human cannabinoid receptor 1 (27,55,56). Using overexpression, purification, and circular dichroism spectroscopy analysis of the fulllength CB1 C terminus as well as different substitution variants, it was demonstrated that it is the level of hydrophobicity rather than specific amino acids that is critical for helix formation and, thus, targeting to the PM of this GPCR (27,55,56).…”

Presynaptic α2-adrenoceptors control the inhibitory action of presynaptic CB1 cannabinoid receptors on prefrontocortical norepinephrine release in the rat

“…1F). Cumulating evidence from transfection experiments on cell lines suggests a major role of the C-terminus of the CB 1 R in heterologous desensitization and G-protein uncoupling (Daigle et al, 2008a,b;Ellis et al, 2006;Stadel et al, 2011). Furthermore, Ellis et al (2006) suggest a novel pharmacological paradigm, whereby ligands modulate the function of receptors for which they have no significant inherent affinity by acting as regulators of receptor heterodimers.…”

Dietary Omega-6/Omega-3 and Endocannabinoids: Implications for Brain Health and Diseases

“…This has been particularly studied in the context of chronic cannabinoid consumption to decipher the mechanisms of addiction. Mechanisms of desensitization and downregulation are not totally elucidated but they probably involve phosphorylation of the receptor and transcription of immediate early genes [112,113]. Interestingly, CB1 receptors do not desensitize at the same rate, depending on the brain structure [113].…”