Journal
CHANNELS
Volume 7, Issue 2, Pages 126-132Publisher
LANDES BIOSCIENCE
DOI: 10.4161/chan.23968
Keywords
ionotropic glutamate receptors; NMDA receptors; reaction mechanism; single-channel kinetics; protein phosphorylation
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Funding
- National Institutes of Health National Institute of Neurological Disorders and Stroke [052669]
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NMDA receptors are glutamate-activated, Ca2+-permeable ion channels with critical roles in synaptic transmission and plasticity. The shape and size of their current is modulated by several kinase/phosphatase systems, and numerous residues located on the receptors' intracellular C-termini are phosphorylated in vivo. To investigate the mechanisms by which phosphorylation may control channel gating, we examined the single-channel behaviors of receptors carrying the S900A or S929A substitution in their GluN2A subunits and thus were rendered resistant to phosphorylation at those sites. We found that the mutations reduced channel open probability primarily by increasing the frequency of desensitized events. The kinetic models we developed revealed complex but similar changes in mechanism for the two mutants, leading to the view that dephosphorylation at either site may cause receptors to activate slower, deactivate faster and desensitize more frequently. This modulatory mechanism is consistent with the proposed roles for these residues in Ca2+-dependent desensitization and calcineurin-mediated reduction of current during brain development.
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