The goal of this research is to characterize signal transduction mechanisms of the CB1 cannabinoid receptor.
The specific aims are to test the following hypotheses: 1. Regulation of specific effectors by CB1 cannabinoid receptors is dependent upon specific G-protein subtype proteins in the N18TG2 neuronal model. 2. The HelixII-asp-Helix VII-asn interaction maintains a conformational constraint on the CB1 receptor that can be modified by Na+, leading to effects on signal transduction that differ with agonist class and G-protein type. The Helix VII-pro distal to the asn can transmit conformational changes important for signal transduction. 3. The HelixVII juxtamembrane C-terminal region regulates interaction with G-proteins, and this regulation is under the influence of structural modifications imposed by palmitoylation/depalmitoylation. 4. Phosphorylations of thr/ser on the CB1 receptor are regulatory mechanisms in CB1 receptor signal transduction. 5. Tyr phosphorylation is a post-translational modification that is a regulatory mechanism for CB1 cannabinoid receptor signal transduction, with particular emphasis on the NPIIY motif in HelixVII. These studies will provide a cohesive analysis of CB1 receptor conformational changes that are necessary to transmit the activating signal to specific G-proteins that mediate various neuronal responses. The emphasis for these studies is the proposed Helix II-Helix VII interaction that is hypothesized to trigger conformational control over the HelixVII juxtamembrane region which activates G-proteins. Specificity for G-proteins and modulation by post-translational modifications are proposed to be key regulatory mechanisms that govern the signal transduction capabilities of the CB1 cannabinoid receptor.
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