This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.
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