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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH100024-05
Application #
9249980
Study Section
Special Emphasis Panel (ZMH1-ERB-L)
Project Start
Project End
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
5
Fiscal Year
2017
Total Cost
$265,338
Indirect Cost
$101,549
Name
Johns Hopkins University
Department
Type
Domestic Higher Education
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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