STRUCTURE AND BIOPHYSICS OF ACETYLCHOLINE RECEPTOR

神经系统中交流的中心是 突触后受体到神经释放的递质。建议数 研究将探索激动剂结合如何触发激活和 烟碱型乙酰胆碱受体(AChR)的脱敏作用 运动性突触。要检查这些触发过程，从功能上 重要的区域将通过在AChR复合体中的表达来识别 带有基因工程突变的亚基。 第一组实验将识别伽马残留物和 对激动剂结合部位有贡献的Delta亚基。这些 研究建立在最近的证据基础上，即结合位点是在 阿尔法亚单位和非阿尔法亚单位之间的界面。 第二组实验将识别结合在一起的残基 五聚体中亚基之间的变构相互作用。这些研究 将为亚基相互作用如何维持AChR带来新的见解 在低亲和力可激活状态下，以及这种相互作用是如何 协同连接两个激动剂结合位点。 最后两组实验将确定AChR的偶联部分 绑定到通道开口。第一组将确定哪些AChR 亚基决定通道门控动力学，而第二个亚基决定通道门控动力学 确定决定胎儿的γ和epsilon亚基的残留物 和成人门控动力学。 了解激动剂结合如何触发激活和脱敏 对理解AChR功能至关重要，而AChR功能又是 了解突触传递和药物在运动终板的作用。 所获得的见解可能会为整个 神经递质门控离子通道超家族。

Central to communication in the nervous system are responses of postsynaptic receptors to nerve-released transmitter. The proposed research will explore how agonist binding triggers activation and desensitization of the nicotinic acetylcholine receptor (AChR) found at motor synapses. To examine these triggering processes, functionally important regions will be identified by expressing in AChR complexes subunits with genetically engineered mutations. The first set of experiments will identify residues of the gamma and delta subunits that contribute to the agonist binding sites. These studies build upon recent evidence that the binding sites are formed at interfaces between alpha and non-alpha subunits. The second set of experiments will identify residues that couple allosteric interactions between subunits in the pentamer. These studies will bring new insights into how subunit interactions maintain the AChR in the low affinity activatable state, as well as how such interactions cooperatively link the two agonist binding sites. Two final sets of experiments will identify parts of the AChR that couple binding to channel opening. The first set will identify what AChR subunits determine channel gating kinetics, while the second will identify residues of the gamma and epsilon subunits that determine fetal and adult gating kinetics. Knowing how agonist binding triggers activation and desensitization is essential to understanding AChR function, which in turn is essential to understanding synaptic transmission and drug action at motor endplates. The insights gained may provide similar insights for the entire superfamily of neurotransmitter-gated ion channels.