Niehaus Jason L, Liu Yunguang, Wallis Kathleen T, Egertová Michaela, Bhartur Sheela G, Mukhopadhyay Somnath, Shi Shanping, He Hengjun, Selley Dana E, Howlett Allyn C, Elphick Maurice R, Lewis Deborah L
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912, USA.
Mol Pharmacol. 2007 Dec;72(6):1557-66. doi: 10.1124/mol.107.039263. Epub 2007 Sep 25.
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).
CB1大麻素受体是一种G蛋白偶联受体，在突触可塑性、镇痛、食欲和神经保护方面具有重要的生理作用。我们报告发现了两种结构相关的CB1大麻素受体相互作用蛋白（CRIP1a和CRIP1b），它们与CB1的远端C末端尾巴结合。CRIP1a和CRIP1b是由人类2号染色体上一个基因的可变剪接产生的，CRIP1a的直系同源物存在于所有脊椎动物中，而CRIP1b似乎是灵长类动物所特有的。CRIP1a与源自大鼠脑匀浆的CB1受体共免疫沉淀，表明CRIP1a和CB1在体内相互作用。此外，在共注射CB1和CRIP1a或CRIP1b cDNA的颈上神经节神经元中，CRIP1a而非CRIP1b抑制CB1介导的电压门控Ca2+通道的强直抑制。CRIP1a的发现为神经系统中CB1调节机制的新研究途径提供了基础，并可能导致开发新型药物来治疗CB1活性调节具有治疗潜力的疾病（如慢性疼痛、肥胖症和癫痫）。
