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.
|Eldeeb, Khalil; Leone-Kabler, Sandra; Howlett, Allyn C (2017) Mouse Neuroblastoma CB1 Cannabinoid Receptor-Stimulated [35S]GTP?S Binding: Total and Antibody-Targeted G? Protein-Specific Scintillation Proximity Assays. Methods Enzymol 593:1-21|
|Singh, Pratishtha; Ganjiwale, Anjali; Howlett, Allyn C et al. (2017) In silico interaction analysis of cannabinoid receptor interacting protein 1b (CRIP1b) - CB1 cannabinoid receptor. J Mol Graph Model 77:311-321|
|Howlett, Allyn C; Abood, Mary E (2017) CB1 and CB2 Receptor Pharmacology. Adv Pharmacol 80:169-206|
|Blume, Lawrence C; Patten, Theresa; Eldeeb, Khalil et al. (2017) Cannabinoid Receptor Interacting Protein 1a Competition with ?-Arrestin for CB1 Receptor Binding Sites. Mol Pharmacol 91:75-86|
|Eldeeb, Khalil; Leone-Kabler, Sandra; Howlett, Allyn C (2016) CB1 cannabinoid receptor-mediated increases in cyclic AMP accumulation are correlated with reduced Gi/o function. J Basic Clin Physiol Pharmacol 27:311-22|
|Blume, Lawrence C; Leone-Kabler, Sandra; Luessen, Deborah J et al. (2016) Cannabinoid receptor interacting protein suppresses agonist-driven CB1 receptor internalization and regulates receptor replenishment in an agonist-biased manner. J Neurochem 139:396-407|
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|Sesay, John S; Gyapong, Reginald N K; Najafi, Leila T et al. (2015) G?i/o-dependent Ca(2+) mobilization and G?q-dependent PKC? regulation of Ca(2+)-sensing receptor-mediated responses in N18TG2 neuroblastoma cells. Neurochem Int 90:142-51|
|Blume, Lawrence C; Eldeeb, Khalil; Bass, Caroline E et al. (2015) Cannabinoid receptor interacting protein (CRIP1a) attenuates CB1R signaling in neuronal cells. Cell Signal 27:716-726|
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