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CB₁ Cannabinoid Receptor Activity Is Modulated by the Cannabinoid Receptor Interacting Protein CRIP 1a

Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia (J.L.N., Y.L., K.T.W., S.G.B., S.S., D.L.L.); School of Biological & Chemical Sciences, Queen Mary, University of London, London, United Kingdom (M.E., M.R.E.); Neuroscience of Drug Abuse Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina, (S.M., A.C.H.); and Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (H.H., D.E.S.)

The CB₁ cannabinoid receptor is a G-protein coupled receptor that has important physiological roles in synaptic plasticity, analgesia, appetite, and neuroprotection. We report the discovery of two structurally related CB₁ cannabinoid receptor interacting proteins (CRIP1a and CRIP1b) that bind to the distal C-terminal tail of CB₁. CRIP1a and CRIP1b are generated by alternative splicing of a gene located on chromosome 2 in humans, and orthologs of CRIP1a occur throughout the vertebrates, whereas CRIP1b seems to be unique to primates. CRIP1a coimmunoprecipitates with CB₁ receptors derived from rat brain homogenates, indicating that CRIP1a and CB₁ interact in vivo. Furthermore, in superior cervical ganglion neurons coinjected with CB₁ and CRIP1a or CRIP1b cDNA, CRIP1a, but not CRIP1b, suppresses CB₁-mediated tonic inhibition of voltage-gated Ca²⁺ channels. Discovery of CRIP1a provides the basis for a new avenue of research on mechanisms of CB₁ regulation in the nervous system and may lead to development of novel drugs to treat disorders where modulation of CB₁ activity has therapeutic potential (e.g., chronic pain, obesity, and epilepsy).

Address correspondence to: Deborah L. Lewis, Ph.D., Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912. Phone: 706-951-6298; E-mail: lewisdebo{at}gmail.com

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