Ogawa Masaaki, Miyakawa Tsuyoshi, Nakamura Kenji, Kitano Jun, Furushima Kenryo, Kiyonari Hiroshi, Nakayama Rika, Nakao Kazuki, Moriyoshi Koki, Nakanishi Shigetada
Department of Systems Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan.
Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14789-94. doi: 10.1073/pnas.0706945104. Epub 2007 Aug 31.
Tamalin is a scaffold protein that interacts with metabotropic glutamate receptors and the kinase-deficient neurotrophin TrkCT1 receptor and forms a protein complex with multiple protein-trafficking and intracellular signaling molecules. In culture, tamalin promotes intracellular trafficking of group 1 metabotropic glutamate receptors through its interaction with guanine nucleotide exchange factor cytohesins and causes actin reorganization and membrane ruffling via the TrkCT1/cytohesin-2 signaling mechanism. However, how tamalin serves its physiological function in vivo has remained elusive. In this study, we generated tamalin knockout (Tam(-/-) KO) mice and investigated behavioral alterations resulting from their deficiency in functional tamalin. Targeted deletion of functional tamalin altered neither the overall brain architecture nor the general behavior of the mice under ordinary conditions. However, Tam(-/-) KO mice showed a decrease in sensitivity to acute morphine-induced hyperlocomotion and morphine analgesic effects in the hot-plate test. Furthermore, tamalin deficiency impaired the ability of the animals to show conditioned place preference after repeated morphine administration and to display locomotor sensitization by chronic cocaine treatment. Upon in vivo microdialysis analysis of the nucleus accumbens, Tam(-/-) KO and wild-type mice showed no genotypic differences in their response patterns of extracellular dopamine and glutamate before or after morphine administration. These results demonstrate that the tamalin scaffold protein plays a unique role in both acute and adaptive behavioral responses to morphine and cocaine and could regulate common neural substrates implicated in drugs of abuse.
塔马林是一种支架蛋白，它与代谢型谷氨酸受体以及激酶缺陷型神经营养因子TrkCT1受体相互作用，并与多种蛋白质转运和细胞内信号分子形成蛋白质复合物。在培养过程中，塔马林通过与鸟嘌呤核苷酸交换因子细胞粘附素相互作用，促进1型代谢型谷氨酸受体的细胞内转运，并通过TrkCT1/细胞粘附素-2信号机制引起肌动蛋白重组和膜褶皱。然而，塔马林在体内如何发挥其生理功能仍不清楚。在本研究中，我们生成了塔马林基因敲除（Tam(-/-) KO）小鼠，并研究了功能性塔马林缺乏导致的行为改变。在正常条件下，功能性塔马林的靶向缺失既未改变小鼠的整体脑结构，也未改变其一般行为。然而，Tam(-/-) KO小鼠在热板试验中对急性吗啡诱导的运动亢进和吗啡镇痛作用的敏感性降低。此外，塔马林缺乏损害了动物在重复给予吗啡后表现出条件性位置偏爱以及通过慢性可卡因处理表现出运动敏感化的能力。在对伏隔核进行体内微透析分析时，Tam(-/-) KO小鼠和野生型小鼠在给予吗啡前后细胞外多巴胺和谷氨酸的反应模式上没有基因型差异。这些结果表明，塔马林支架蛋白在对吗啡和可卡因的急性和适应性行为反应中发挥独特作用，并可能调节与滥用药物相关的共同神经底物。
