Regulation of GluA1 phosphorylation by the neuropeptide PACAP38
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Date
2015-07-06
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Johns Hopkins University
Abstract
Dynamic changes in synaptic strength are thought to be critical for higher brain function such as learning and memory. Alterations in synaptic strength result from modulation of AMPA receptor function and trafficking to synaptic sites. The phosphorylation state of AMPA receptor subunits is one mechanism by which cells regulate receptor function and membrane trafficking. Receptor phosphorylation is in turn regulated by extracellular signals; these include neuronal activity and signaling though neuromodulators such as dopamine, norepinephrine as well as neuropeptides. Although numerous studies have reported that the neuropeptide PACAP38 alters CA1 synaptic strength and GluA1 synaptic localization, its effect on AMPA receptor phosphorylation state has not been explored. We determined that PACAP38-mediated stimulation of hippocampal cultures increased phosphorylation of S845, and decreased phosphorylation of T840 on the GluA1 AMPA receptor subunit. Increases in GluA1 S845 phosphorylation primarily occurred via PAC1 and VPAC2 receptor activation, whereas a reduction in GluA1 T840 phosphorylation was largely driven by PAC1 receptor activation and to a lesser extent by VPAC1 and VPAC2 receptor activation. GluA1 S845 phosphorylation could be blocked by a PKA inhibitor, and GluA1 T840 dephosphorylation could be blocked by a PP1/PP2A inhibitor and was partly blocked by a NMDA receptor antagonist. These results demonstrate that the neuropeptide PACAP38 inversely regulates the phosphorylation of two distinct sites on GluA1 and may play an important role modulating AMPA receptor function and synaptic plasticity in the brain.
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AMPA receptor phosphorylation