Regulation of Proteasomal Function by Nicotine

描述（由申请人提供）：全世界有超过10亿男性、女性和儿童吸烟，烟草仍然是发达国家过早死亡的最大单一原因。尼古丁是烟草的主要成瘾成分，产生与尼古丁成瘾相关的神经生理、动机和行为变化。了解尼古丁的精神活性作用的神经药理学、解剖学和行为学基础是确定新的治疗靶点和开发对抗尼古丁依赖的新药的关键。这一提议源于实验室最近的数据，这些数据指出了尼古丁的一种新的作用机制。我们现在表明，药物可以通过阻断蛋白酶体活性来改变支架蛋白和神经递质受体的成熟和周转。我们的数据表明，尼古丁对蛋白酶体的影响通过nAChR介导和nAChR非依赖性机制发生。这些结果提供了一种机制，可以解释尼古丁的一些作用，包括药物诱导的蛋白质水平变化和nAChR上调。这项探索性资助将继续对蛋白酶体/尼古丁相互作用的体内和体外机制进行表征。为了确定尼古丁对蛋白酶体的影响是否是尼古丁药理作用的机制之一，我们将研究尼古丁对蛋白酶体功能受到蛋白酶体抑制剂或蛋白酶体成分诱导性敲除干扰的小鼠的行为影响。其他生化和药理学实验将提供有关尼古丁/蛋白酶体相互作用性质的信息。尼古丁对蛋白酶体影响的研究不仅对尼古丁对大脑的影响很重要，而且还将为烟草对不表达nAChR的组织和器官的影响提供新的见解。

DESCRIPTION (provided by applicant): Over a billion men, women and children worldwide smoke, and tobacco continues to be the largest single cause of premature death in developed countries. Nicotine, the main addictive component of tobacco, produces the neurophysiological, motivational and behavioural changes associated with nicotine addiction. Understanding the neuropharmacological, anatomical and behavioural underpinnings of the psychoactive effects of nicotine is key for the identification of new therapeutical targets and the development of new drugs against nicotine dependence. This proposal stems from recent data in the lab that pinpoint a novel mechanism of action for nicotine. We now show that the drug can change maturation and turnover of scaffolding proteins and neurotransmitter receptors by blocking proteasomal activity. Our data indicate that nicotine's effects on the proteasome occur via both nAChR-mediated and nAChR- independent mechanisms. These results provide a mechanism that could explain some of the effects of nicotine, including the drug-induced changes in protein levels, and nAChR upregulation. This exploratory grant will continue the characterization of the proteasome/nicotine interaction with both in vivo and in vitro mechanisms. To determine whether nicotine's influence on the proteasome is one of the mechanisms underlying the pharmacological effects of nicotine we will examine the behavioral effects of nicotine in mice in which proteasomal function is perturbed by proteasomal inhibitors or the inducible knockout of a proteasomal component. Other biochemical and pharmacological experiments will provide information on the nature of the nicotine/proteasome interaction. The investigation of nicotine's influence on the proteasome is important not only for the effects of nicotine on the brain but it will also provide new insights on the effects of tobacco on tissues and organs that do not express nAChRs.