Our long-term goal is to understand how rapidly-activated synaptic receptors convert a chemical signal into an electrical one, and how disease and therapeutic drugs alter this process. The process of chemo-electrical transduction is fundamental to the proper functioning of the nervous system, yet its mechanistic and structural bases are poorly understood. Toward understanding chemo-electrical transduction, the proposed studies will determine how the neurotransmitter acetylcholine (ACh) activates ACh receptors (AChRs) from voluntary skeletal muscle and alpha7 AChRs from neurons and cells of the inflammatory system. In particular, we will address major gaps in understanding the activation mechanism through a combination of high resolution single channel recording, kinetic analyses and structural perturbations. First, we will define elementary reaction steps that underlie AChR activation, and then identify structures that mediate each reaction step. Second, we will delineate structural and mechanistic bases of agonist efficacy. Third, we will define structural underpinnings of cooperativity in AChR activation. Completion of this project will yield both mechanistic and structural understanding of chemo-electrical transduction applicable to therapeutic drug design and treatment of neurological diseases including muscle weakness disorders, Parkinson's and Alzheimer's diseases and schizophrenia.
Nicotinic acetylcholine receptors (AChRs) mediate cell-cell communication throughout the nervous system, and are associated with a broad spectrum of neurological diseases, including congenital myasthenic syndromes, epilepsy, Alzheimer's and Parkinson's diseases, schizophrenia and nicotine addiction. This project will delineate mechanisms of chemo-electrical transduction by AChRs from skeletal muscle, given their central role in neuromuscular disease, and by alpha 7 AChRs from neurons and cells of the inflammatory system, given their relevance to psychiatric and neurodegenerative diseases. The resulting mechanistic understanding will enable rational treatment of neurological diseases and form bases to develop therapeutic drugs.
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