The CB 1 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 CB 1 cannabinoid receptor interacting proteins (CRIP1a and CRIP1b) that bind to the distal C-terminal tail of CB 1 . 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 CB 1 receptors derived from rat brain homogenates, indicating that CRIP1a and CB 1 interact in vivo. Furthermore, in superior cervical ganglion neurons coinjected with CB 1 and CRIP1a or CRIP1b cDNA, CRIP1a, but not CRIP1b, suppresses CB 1 -mediated tonic inhibition of voltage-gated Ca 2ϩ channels. Discovery of CRIP1a provides the basis for a new avenue of research on mechanisms of CB 1 regulation in the nervous system and may lead to development of novel drugs to treat disorders where modulation of CB 1 activity has therapeutic potential (e.g., chronic pain, obesity, and epilepsy).G protein-coupled receptors (GPCRs) provide a wide range of signaling capabilities to regulate the activity of downstream cellular targets. To signal efficiently, cells must be able to dynamically control the activity of GPCRs. Although some regulatory pathways, such as desensitization and internalization mediated by ␤-arrestin (Benovic et al., 1986), are applicable to most GPCRs, specialized means of regulation for particular GPCRs have been identified. Because many GPCRs have been shown to have spontaneous basal activity, ancillary proteins that interact with GPCRs may prove to be specific modulators of this activity. A prominent protein-protein interaction site studied on GPCRs is the C-terminal tail; G-protein binding and post-translational modifications occur in this region in many GPCRs. The profound sequence variety of C-terminal tails provides a means for selectivity in G-protein interactions as well as diversity in receptor trafficking. The G-protein-coupled receptor-associated sorting protein GASP1 interacts with the C-terminal tail of many GPCRs, including CB 1 , resulting in down-regulation and degradation (Martini et al., 2007). The adaptor protein FAN is also able to interact with the CB 1 receptor

In superior cervical ganglion neurons, N-(piperidiny-1-yl)-5-(4-