Glutamate-AMPA receptors are the key mediators of excitatory transmission of which GluA1 is a major subtype. GluA1's conductance is critically determined by phosphorylation at serine-831. We recently discovered that nitric oxide (NO) nitrosylates GluA1 at a specific cysteine, C875. and that this nitrosylation determines S831 phosphorylation. We plan to elucidate mechanisms underlying this important mode of regulation. We will also explore the impact of hydrogen sulfide (H2S) modifying, via sulfhydration, C875 in presumed reciprocity with nitrosylation. We earlier showed that nitrosylation of stargazin, a major auxiliary protein of AMPA receptors, determines GluA1 conductance. We will explore regulation of this process and how it interfaces with gasotransmitter influences exerted directly upon GluA1.

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Learning, memory and other major brain functions are determined by neurotransmission involving the amino acid glutamate acting upon AMPA receptors. Our research shows how gasotransmitters. molecules such as nitric oxide and hydrogen sulfide, regulate these processes. This work clarifies fundamental aspects of brain function and affords an avenue to developing therapeutic agents for brain disease.

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National Institute of Mental Health (NIMH)
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Johns Hopkins University
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