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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-3 (03))
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Rapaka, Rao
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North Carolina Central University
Schools of Arts and Sciences
United States
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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
Luessen, Deborah J; Hinshaw, Tyler P; Sun, Haiguo et al. (2016) RGS2 modulates the activity and internalization of dopamine D2 receptors in neuroblastoma N2A cells. Neuropharmacology 110:297-307
Conner-Kerr, Teresa; Malpass, Gloria; Steele, Arhalia et al. (2015) Effects of 35 kHz, low-frequency ultrasound application in vitro on human fibroblast morphology and migration patterns. Ostomy Wound Manage 61:34-41
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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