Functional characterization of cannabinoid receptor‐interacting protein CRIP1a

Abstract

G‐protein‐coupled CB 1 cannabinoid receptors (CB 1 Rs) are highly expressed in the brain and together with the endocannabinoids, anandamide and 2‐arachidonoylglycerol (2‐AG), modulate appetite, reward, pain, memory and motor activity. Cannabinoid receptor‐interacting protein 1a (CRIP 1a ) is a novel regulatory protein that binds to the C‐terminus of CB 1 Rs but not CB 2 Rs. Studies in cell models in which CRIP 1a was co‐expressed with CB 1 Rs at a molar ratio of 5:1, respectively, showed that CRIP 1a did not alter CB 1 R expression levels but inhibited agonist‐stimulated and constitutive CB 1 R‐mediated G‐protein activation, as determined by [ 35 S]GTPγS binding. Electrophysiological studies in cultured hippocampal neurons showed that CRIP 1a over‐expression attenuated 2‐AG‐mediated inhibition of excitatory synaptic activity. These results suggest that CRIP 1a negatively regulates CB 1 R signaling. To determine effects of loss of CRIP 1a function, we generated Cnrip1 genetic null mice. Cnrip1 null mice are viable and do not express CRIP 1a protein in the brain or spinal cord, thus providing a valuable tool to assess CRIP 1a function in vivo. Supported by R21‐ DA025321 and R01‐DA030404 from NIDA and an A.D. Williams Multischool Award.