GENERAL ANESTHETIC MECHANISM IN EXCITABLE MEMBRANES

描述：（改编自申请人的摘要）总体 本提案的目的是阐明分子机制， 哪种全身麻醉剂会导致昏迷由于离子通道 介导CNS细胞内和细胞间的通讯，它们是 被认为是麻醉剂的“目标”。为了 研究全身麻醉药作用于 关于CNS中的膜兴奋性，申请人特别提出 研究不同麻醉剂对配体门控离子的影响， 通道，包括mAChR，GABAA受体和nAChR。基本 假设是麻醉剂直接与离子通道蛋白结合。 现在的具体目标包括：1）研究麻醉剂对 mAChR通道在通道孔内具有突变， 以便确定麻醉剂在孔内的何处结合以及是否结合; 2)确定麻醉剂对GABAA受体通道的影响 并观察这是否与对AChR通道的影响相似; 3） 为了确定麻醉剂对神经元AChR通道的作用是否 类似于对肌肉AChR通道的作用;以及4）确定 神经元AChR和GABAA受体的不同亚型是否 通道对麻醉剂具有不同的敏感性。转染的HEK 含有感兴趣的配体门控离子通道的细胞是模型 系统使用。

DESCRIPTION: (Adapted from the applicant's abstract) The overall objective of this proposal is to elucidate the molecular mechanisms by which general anesthetics produce unconsciousness. Since ion channels mediate communication within and between cells in the CNS, they are considered likely candidates as the "targets" of anesthetics. In order to investigate molecular mechanisms of action of general anesthetics on membrane excitability in the CNS, the applicant proposes specifically to examine the effects of different anesthetics on ligand gated ion channels, including the mAChR, GABAA receptor, and the nAChR. The basic hypothesis is that anesthetics bind directly to ion channel proteins. Specific aims now include: 1) to study the effect of anesthetics on mAChR channels which have mutations within the pore of the channel in order to determine where and whether anesthetics bind within the pore; 2) to determine the effects of anesthetics on GABAA receptor channels and to see whether this is similar to the effects on AChR channels; 3) to determine whether the action of anesthetics on neuronal AChR channels is similar to the action on muscle AChR channels; and 4) to determine whether the different isoforms of neuronal AChR and GABAA receptor channels have different sensitivities to anesthetics. Transfected HEK cells containing the ligand gated ion channel of interest is the model system utilized.