Excitatory neurotransmission in the central nervous system is mediated largely by the neurotransmitter glutamate acting on specific glutamate receptors. It is well known that the efficiency of transmission at these glutamatergic synapses can be decreased (long-term depression) or enhanced (long-term potentiation) for prolonged periods of time. This synaptic plasticity is due to both alterations in the release of neurotransmitter (presynaptic mechanism) and in the responsiveness of the postsynaptic neuron. This grant application will investigate several Ca2+ dependent mechanisms that may account for postsynaptic changes in glutamate receptor ion channels (GluRs). Results from our laboratory, as well as from several other research groups, has provided strong evidence that a key player in these postsynaptic Ca2+ dependent changes is phosphorylation of glutamate receptor ion channels (GluRs) by Ca2+/calmodulin-dependent protein kinase II (CaM-K II) and perhaps dephosphorylation by calcineurin. This grant application will investigate regulatory functions of CaM-K II and calcineurin on all three types of GluRs.
The specific aims are: l. Investigate the phosphorylation and regulation of AMPA-type GluRs by CaM-K II and protein phosphatases. 2. Investigate the regulation of kainate-type GluRs by CaM-K II. 3. Determine the roles of protein kinases and phosphatases in two Ca2+ dependent modulations of NMDA-type GluRs. These studies will include both biochemical, molecular biological and electrophysiological techniques using cultured hippocampal neurons and the various GluRs expressed in HEK 293 cells. The results of these studies have strong implications for modulating synaptic efficiency in paradigms of learning and memory and for neuronal excitability in epilepsy.
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