SATBILIZATION OF ALPHA4, BETA2, ALPHA7 NACHRS USING COMPUTATIONAL METHODS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 中枢神经系统负责协调身体的各种过程。乙酰胆碱作为一种神经递质在中枢神经系统中起着重要的作用，可以引起多种细胞反应。乙酰胆碱神经递质的主要活动是肌肉组织的兴奋。乙酰胆碱通过与细胞膜上的乙酰胆碱受体结合而与靶细胞相互作用。烟碱型乙酰胆碱受体(NAChRs)是一种膜结合型乙酰胆碱受体蛋白。这些受体也可能是麻醉药物相互作用的靶点。大多数受体蛋白与麻醉药物相互作用的研究在技术上具有挑战性，这是因为膜蛋白的分离困难，以及使用核磁共振(NMR)来高分辨率阐明受体结构的局限性。在膜内，神经递质离子门控通道和膜蛋白的环状区域被认为是与全身麻醉药相互作用的部位。到目前为止，研究表明，nAChRs是由各种蛋白质亚基组成的，这些亚基跨越膜并延伸到细胞外，而受体的孔位于膜内，周围有一个框架将其与膜内的脂类分开。神经元nAChR可以由不同的亚基组成，例如由两个A4和三个b2亚基组成的异构体nAChR，或者包含五个A7亚基的同质nAChR。我们的最终目标是了解麻醉药影响神经系统的机制。为了达到这一目标，将使用计算方法试图找到b2和a7神经元nAChRs和A1甘氨酸受体的突变，这些突变在较低的pH下更稳定。将使用模拟和结构确定的计算方法来努力稳定nAChRs跨膜区的A4、b2和A7蛋白。A1甘氨酸受体也将进行类似的研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The central nervous system is responsible for coordinating the various processes of the body. Acetylcholine plays an important role in the central nervous system as a neurotransmitter that elicits a variety of cellular responses. The main activity of the acetylcholine neurotransmitter is the excitation of muscle tissue. Acetylcholine interacts with its target cells by binding to acetylcholine receptors in cellular membranes. Nicotinic acetylcholine receptors (nAChRs) are an example of membrane-bound acetylcholine receptor proteins. These receptors are also putative targets of interaction with anesthetic drugs. Most study of the interaction between receptor proteins and anesthetic drugs is technically challenging due to the difficulty of isolating membrane proteins and limitations when using nuclear magnetic resonance (NMR) to elucidate receptor structure at a high resolution. Within the membrane, both neurotransmitter ion-gated channels and cys-loop regions of membranous proteins have been implicated as sites of interaction with general anesthetics. Studies have thus far demonstrated that nAChRs are composed of various protein subunits which span the membrane and extend extracellularly while the pore of the receptor is located inside the membrane with a surrounding frame that separates it from the lipids within the membrane. Neuronal nAChRs can be composed of different subunits, such as a heteromeric nAChR of two a4 and three b2 subunits, or a homomeric nAChR containing five a7 subunits. Our ultimate goal is to gain an understanding of the mechanism by which anesthetic drugs affect the nervous system. In order to reach this goal, computational methods will be used in an attempt to find mutations of the b2 and a7 neuronal nAChRs and the a1 glycine receptor that are more stable at a lower pH. Computational methods of simulation and structural determination will be used in an effort to stabilize the a4, b2, and a7 proteins of the transmembrane domain of the nAChRs. The a1 glycine receptor will also be studied similarly.