Regulation of AMPA receptor phosphorylation by the neuropeptide PACAP38.
Dynamic changes in synaptic strength are thought to be critical for higher brain function such as learning and memory. Alterations in synaptic strength can result from modulation of AMPA receptor (AMPAR) function and trafficking to synaptic sites. The phosphorylation state of AMPAR subunits is one mechanism by which cells regulate receptor function and trafficking. Receptor phosphorylation is in turn regulated by extracellular signals; these include neuronal activity, neuropeptides, and neuromodulators such as dopamine and norepinephrine (NE). Although numerous studies have reported that the neuropeptide pituitary adenylate cyclase activating polypeptide 38 (PACAP38) alters hippocampal CA1 synaptic strength and GluA1 synaptic localization, its effect on AMPAR phosphorylation state has not been explored. We determined that PACAP38 stimulation of hippocampal cultures increased phosphorylation of S845, and decreased phosphorylation of T840 on the GluA1 AMPAR 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 protein phosphatase 1/2A (PP1/PP2A) inhibitor and was partly blocked by a NMDA receptor (NMDAR) 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 AMPAR function and synaptic plasticity in the brain.
['Toda|Alyssa M A|AM|', 'Huganir|Richard L|RL|']
D000818:Animals D001665:Binding Sites D056547:CA1 Region, Hippocampal D002478:Cells, Cultured D017868:Cyclic AMP-Dependent Protein Kinases D019706:Excitatory Postsynaptic Potentials D051379:Mice D010749:Phosphoprotein Phosphatases D010766:Phosphorylation D051219:Pituitary Adenylate Cyclase-Activating Polypeptide D051381:Rats D018091:Receptors, AMPA D016194:Receptors, N-Methyl-D-Aspartate D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I D051239:Receptors, Vasoactive Intestinal Peptide, Type II D009435:Synaptic Transmission
AMPA receptor phosphorylation PACAP38 synaptic transmission