Inhibitory Interactions between Phosphorylation Sites in the C Terminus of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid-type Glutamate Receptor GluA1 Subunits
Copyright policy )Inhibitory Interactions between Phosphorylation Sites in the C Terminus of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid-type Glutamate Receptor GluA1 Subunits
The C terminus of AMPA-type glutamate receptor (AMPAR) GluA1 subunits contains several phosphorylation sites that regulate AMPAR activity and trafficking at excitatory synapses. Although many of these sites have been extensively studied, little is known about the signaling mechanisms regulating GluA1 phosphorylation at Thr-840. Here, we report that neuronal depolarization in hippocampal slices induces a calcium and protein phosphatase 1/2A-dependent dephosphorylation of GluA1 at Thr-840 and a nearby site at Ser-845. Despite these similarities, inhibitors of NMDA-type glutamate receptors and protein phosphatase 2B prevented depolarization-induced Ser-845 dephosphorylation but had no effect on Thr-840 dephosphorylation. Instead, depolarization-induced Thr-840 dephosphorylation was prevented by blocking voltage-gated calcium channels, indicating that distinct Ca(2+) sources converge to regulate GluA1 dephosphorylation at Thr-840 and Ser-845 in separable ways. Results from immunoprecipitation/depletion assays indicate that Thr-840 phosphorylation inhibits protein kinase A (PKA)-mediated increases in Ser-845 phosphorylation. Consistent with this, PKA-mediated increases in AMPAR currents, which are dependent on Ser-845 phosphorylation, were inhibited in HEK-293 cells expressing a Thr-840 phosphomimetic version of GluA1. Conversely, mimicking Ser-845 phosphorylation inhibited protein kinase C phosphorylation of Thr-840 in vitro, and PKA activation inhibited Thr-840 phosphorylation in hippocampal slices. Together, the regulation of Thr-840 and Ser-845 phosphorylation by distinct sources of Ca(2+) influx and the presence of inhibitory interactions between these sites highlight a novel mechanism for conditional regulation of AMPAR phosphorylation and function.
- University of California, Los Angeles United States
- University of California, San Francisco United States
Threonine, Male, Biomedical and clinical sciences, Medical Physiology, Glutamate Receptors Ionotropic, Inbred C57BL, Medical and Health Sciences, Hippocampus, Protein Phosphorylation, Membrane Potentials, Mice, Protein Phosphatase 1, Receptors, AMPA, Serine, 2.1 Biological and endogenous factors, Protein Phosphatase 2, Aetiology, Phosphorylation, Oxazoles, Protein Kinase C, Neurons, Blotting, Biological Sciences, Biological sciences, Western, 570, Biochemistry & Molecular Biology, Blotting, Western, 610, GluA1 Subunits, AMPA Receptor, Okadaic Acid, Animals, Humans, Binding Sites, Biomedical and Clinical Sciences, Cyclic AMP-Dependent Protein Kinases, Mice, Inbred C57BL, Protein Subunits, HEK293 Cells, Chemical sciences, Chemical Sciences, Protein Phosphatase, Calcium, Marine Toxins, Biochemistry and Cell Biology, Calcium Channels, Protein Kinases, Synaptic Plasticity
Threonine, Male, Biomedical and clinical sciences, Medical Physiology, Glutamate Receptors Ionotropic, Inbred C57BL, Medical and Health Sciences, Hippocampus, Protein Phosphorylation, Membrane Potentials, Mice, Protein Phosphatase 1, Receptors, AMPA, Serine, 2.1 Biological and endogenous factors, Protein Phosphatase 2, Aetiology, Phosphorylation, Oxazoles, Protein Kinase C, Neurons, Blotting, Biological Sciences, Biological sciences, Western, 570, Biochemistry & Molecular Biology, Blotting, Western, 610, GluA1 Subunits, AMPA Receptor, Okadaic Acid, Animals, Humans, Binding Sites, Biomedical and Clinical Sciences, Cyclic AMP-Dependent Protein Kinases, Mice, Inbred C57BL, Protein Subunits, HEK293 Cells, Chemical sciences, Chemical Sciences, Protein Phosphatase, Calcium, Marine Toxins, Biochemistry and Cell Biology, Calcium Channels, Protein Kinases, Synaptic Plasticity
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