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

Genetic factors are known to be important in the development of prostate cancer. Interleukin-18 (IL-18) is a multifunctional cytokine that induces interferon-gamma secretion and plays an important role in antitumor immunity. Variations in the DNA sequence in the IL-18 gene promoter may lead to altered IL-18 production and/or activity, and so this can modulate an individual's susceptibility to prostate cancer. To test this hypothesis, we investigated the relationship of IL-18 gene promoter -137 G/C and -607 C/A polymorphisms and their haplotypes with the risk of prostate cancer. We analyzed two single nucleotide polymorphisms of IL-18 gene promoter -137 G/C and -607 C/A in 265 patients with prostate cancer and 280 age- and sex-matched controls, using sequence-specific primers-polymerase chain reaction strategy. There were significant differences in the genotype and allele distribution of -137 G/C polymorphism of the IL-18 gene among cases and controls. The -137 GC and CC genotypes were associated with a significantly increased risk of prostate cancer as compared with the -137 GG genotypes [odds ratio (OR) = 1.721; 95% confidence interval (CI): 1.187-2.496; p = 0.004, and OR = 2.181; 95% CI: 1.034-4.603; p = 0.037, for GC and CC, respectively]. Consistent with the results of the genotyping analyses, the -137C/-607A haplotype was associated with a significantly increased risk of prostate cancer as compared with the -137G/-607C haplotype (OR = 1.544; 95% CI, 1.137-2.096; p = 0.005). This study shows for the first time an association between IL-18 gene promoter -137 G/C polymorphism and prostate cancer in a Chinese population.

This study shows for the first time an association between IL-18 gene promoter -137 G/C polymorphism may contribute represent a genetic risk factor for ESCC in a Chinese population.

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