GENERAL ANESTHETIC MECHANISM IN EXCITABLE MEMBRANES

描述：(改编自申请人的摘要)总体情况 这项建议的目的是阐明分子机制，通过 哪种全身麻醉药会导致昏迷。由于离子通道 调节中枢神经系统中细胞内部和细胞之间的通信，它们是 被认为可能是麻醉剂的“靶子”。按顺序 探讨全麻药对血管紧张素转换酶影响的分子机制 中枢神经系统中的膜兴奋性，申请人特别提出 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。最基本的 假说是麻醉剂直接与离子通道蛋白结合。 目前的具体目标包括：1)研究麻醉剂对 MAChR通道在通道的孔洞内发生突变 以确定麻醉剂在哪里以及是否在毛孔内结合； 2)测定麻醉药对GABAA受体通道的影响 并看看这是否类似于对AChR通道的影响；3) 确定麻醉药对神经元型AChR通道的作用 类似于对肌肉AChR通道的作用；以及4)确定 神经元型AChR和GABAA受体的不同亚型 通道对麻醉药有不同的敏感性。转染型HEK 含有配体门控离子通道的细胞是模型 系统已使用。

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.