Delta-9-Tetrahydrocannabinol(delta-9 THC)is the primary CNS-active component of Cannabis sativa. Cannabinoid analgetics, including desacetyllevonantradol and CP-55940, potently mimic the effects of delta-9 THC in a number of animal models. Using these potent cannabinoid compounds, my laboratory determined that the cellular mechanism of action of the CNS-active cannabinoid drugs was to inhibit adenylate cyclase via G-i. We radiolabeled CP-55940 and developed a receptor binding assay to biochemically characterize the cannabinoid receptor. This work will continue with the following goals: 1. Characterization of the cellular regulation of the cannabinoid receptor in neuronal cells including synthesis, post-translational processing, transit to the plasma membrane, and potential sequestration in response to chronic agonist stimulation; 2. Characterization of the structural properties of the cannabinoid receptor and determination of the functional concomitants; 3. Purification of the cannabinoid receptor and use of the purified protein for structure analysis, antibody production, reconstitution with signal transducing G-proteins and to purify an endogenous cannabinoid-like binding activity for the cannabinoid receptor. 4. Identification of an endogenous cannabinoid-like binding activity present in the CNS, and purification ana characterization of the factor(s) responsible for this action at the cannabinoid receptor. Production of antibodies for the endogenous cannabinoid-like binding factor(s) and development of immunoassays.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Award (K05)
Project #
1K05DA000182-01
Application #
3075477
Study Section
Special Emphasis Panel (SRCD (10))
Project Start
1992-08-01
Project End
1997-07-31
Budget Start
1992-08-01
Budget End
1993-07-31
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Saint Louis University
Department
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Oddi, Sergio; Dainese, Enrico; Sandiford, Simone et al. (2012) Effects of palmitoylation of Cys(415) in helix 8 of the CB(1) cannabinoid receptor on membrane localization and signalling. Br J Pharmacol 165:2635-51
Gerald, Tonya M; Howlett, Allyn C; Ward, Gregg R et al. (2008) Gene expression of opioid and dopamine systems in mouse striatum: effects of CB1 receptors, age and sex. Psychopharmacology (Berl) 198:497-508
Jones, Jenelle D; Carney, Skyla T; Vrana, Kent E et al. (2008) Cannabinoid receptor-mediated translocation of NO-sensitive guanylyl cyclase and production of cyclic GMP in neuronal cells. Neuropharmacology 54:23-30
Grace, Christy R R; Cowsik, Sudha M; Shim, Joong-Youn et al. (2007) Unique helical conformation of the fourth cytoplasmic loop of the CB1 cannabinoid receptor in a negatively charged environment. J Struct Biol 159:359-68
Ward, Gregg R; Franklin, Steven O; Gerald, Tonya M et al. (2007) Glucocorticoids plus opioids up-regulate genes that influence neuronal function. Cell Mol Neurobiol 27:651-60
McCollum, LaTronya; Howlett, Allyn C; Mukhopadhyay, Somnath (2007) Anandamide-mediated CB1/CB2 cannabinoid receptor--independent nitric oxide production in rabbit aortic endothelial cells. J Pharmacol Exp Ther 321:930-7
Mukhopadhyay, Somnath; Das, Sucharita; Williams, Evelyn A et al. (2006) Lipopolysaccharide and cyclic AMP regulation of CB(2) cannabinoid receptor levels in rat brain and mouse RAW 264.7 macrophages. J Neuroimmunol 181:82-92
Gerald, Tonya M; Ward, Gregg R; Howlett, Allyn C et al. (2006) CB1 knockout mice display significant changes in striatal opioid peptide and D4 dopamine receptor gene expression. Brain Res 1093:20-4
Shim, Joong-Youn; Howlett, Allyn C (2006) WIN55212-2 docking to the CB1 cannabinoid receptor and multiple pathways for conformational induction. J Chem Inf Model 46:1286-300
Howlett, Allyn C (2005) A short guide to the nomenclature of seven-transmembrane spanning receptors for lipid mediators. Life Sci 77:1522-30

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