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The Journal of Neuroscience, November 15, 2001, 21(22):8758-8764

Structural Domains of the CB1 Cannabinoid Receptor That Contribute to Constitutive Activity and G-Protein Sequestration

Jingjiang Nie and Deborah L. Lewis

Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912

The CB1 cannabinoid receptor is a constitutively active receptor that can sequester G_i/o-proteins and prevent other G_i/o-coupled receptors from signaling (Bouaboula et al., 1997; Pan et al., 1998; Vasquez and Lewis, 1999). G-protein sequestration occurs because the population of CB1 cannabinoid receptors exists in both an inactive G-protein-precoupled RG_GDP state and a constitutively active R*G_GTP state. We tested the hypothesis that the distal C-terminal tail acts to prevent G-protein activation. We found that truncation of the distal C-terminal tail of the CB1 receptor (CB1-417) enhanced both the constitutive activity and the ability of the receptor to sequester G-proteins. In addition, we tested the hypothesis that the conserved aspartate (D2.50) in the second transmembrane domain of the CB1 cannabinoid receptor is crucial for constitutive activity and G-protein sequestration. We found that the mutation of aspartate to asparagine (CB1-D164N) abolished G-protein sequestration and constitutive receptor activity without disrupting agonist-stimulated activity. We conclude that the CB1-D164N mutation and the C-terminal truncation shift the population of receptors in opposite directions. The CB1-D164N mutation shifts the receptor into an inactive R state upcoupled from G-proteins, whereas the C-terminal truncation (CB1-417) shifts the receptor into the active R*G_GTP state. Thus the distal C-terminal tail acts to constrain the receptor from activating G-proteins, whereas the aspartate (D2.50) in the second transmembrane domain stabilizes the receptor in both the inactive RG_GDP state and the active R*G_GTP state.

Key words: G-protein-coupled receptors; patch clamp; calcium channels; constitutive activity; receptor states; cannabinoid; tonic activity; C terminal

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21228758-07$05.00/0

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