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.
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