APCCdh1 mediates EphA4-dependent downregulation of AMPA receptors in homeostatic plasticity
Copyright policy )APCCdh1 mediates EphA4-dependent downregulation of AMPA receptors in homeostatic plasticity
Homeostatic plasticity is crucial for maintaining neuronal output by counteracting unrestrained changes in synaptic strength. Chronic elevation of synaptic activity by bicuculline reduces the amplitude of miniature excitatory postsynaptic currents (mEPSCs), but the underlying mechanisms of this effect remain unclear. We found that activation of EphA4 resulted in a decrease in synaptic and surface GluR1 and attenuated mEPSC amplitude through a degradation pathway that requires the ubiquitin proteasome system (UPS). Elevated synaptic activity resulted in increased tyrosine phosphorylation of EphA4, which associated with the ubiquitin ligase anaphase-promoting complex (APC) and its activator Cdh1 in neurons in a ligand-dependent manner. APC(Cdh1) interacted with and targeted GluR1 for proteasomal degradation in vitro, whereas depletion of Cdh1 in neurons abolished the EphA4-dependent downregulation of GluR1. Knockdown of EphA4 or Cdh1 prevented the reduction in mEPSC amplitude in neurons that was a result of chronic elevated activity. Our results define a mechanism by which EphA4 regulates homeostatic plasticity through an APC(Cdh1)-dependent degradation pathway.
- Hong Kong Polytechnic University China (People's Republic of)
- University of Hong Kong (香港大學) China (People's Republic of)
- Hong Kong University of Science and Technology (香港科技大學) China (People's Republic of)
Excitatory Postsynaptic Potentials: drug effects, Hippocampus, Hippocampus: drug effects, Miniature Postsynaptic Potentials: physiology, Receptors, RNA, Small Interfering, Neurons: drug effects, Cells, Cultured, Neuronal Plasticity: drug effects, Neurons, Cultured, Neuronal Plasticity, Statistics, Miniature Postsynaptic Potentials, Receptor, EphA4, Ubiquitin-Protein Ligase Complexes, Electrophysiology, Hippocampus: physiology, Down-Regulation: drug effects, Excitatory Postsynaptic Potentials: physiology, AMPA: genetics, Neurons: physiology, Receptor, Ubiquitination: drug effects, Proteasome Endopeptidase Complex, Synapses: physiology, Cells, GABA-A Receptor Antagonists: pharmacology, Down-Regulation, Small Interfering, Bicuculline, Miniature Postsynaptic Potentials: drug effects, Anaphase-Promoting Complex-Cyclosome, Statistics, Nonparametric, Neuronal Plasticity: physiology, Hippocampus: cytology, Bicuculline: pharmacology, Animals, Nonparametric, GABA-A Receptor Antagonists, Receptors, AMPA, Ubiquitin-Protein Ligase Complexes: genetics, Neurons: cytology, Analysis of Variance, Proteasome Endopeptidase Complex: metabolism, Down-Regulation: physiology, Excitatory Postsynaptic Potentials, AMPA: metabolism, EphA4: metabolism, Synapses, RNA, Ubiquitination: physiology, Proteasome Endopeptidase Complex: genetics, Synapses: drug effects, Ubiquitin-Protein Ligase Complexes: metabolism
Excitatory Postsynaptic Potentials: drug effects, Hippocampus, Hippocampus: drug effects, Miniature Postsynaptic Potentials: physiology, Receptors, RNA, Small Interfering, Neurons: drug effects, Cells, Cultured, Neuronal Plasticity: drug effects, Neurons, Cultured, Neuronal Plasticity, Statistics, Miniature Postsynaptic Potentials, Receptor, EphA4, Ubiquitin-Protein Ligase Complexes, Electrophysiology, Hippocampus: physiology, Down-Regulation: drug effects, Excitatory Postsynaptic Potentials: physiology, AMPA: genetics, Neurons: physiology, Receptor, Ubiquitination: drug effects, Proteasome Endopeptidase Complex, Synapses: physiology, Cells, GABA-A Receptor Antagonists: pharmacology, Down-Regulation, Small Interfering, Bicuculline, Miniature Postsynaptic Potentials: drug effects, Anaphase-Promoting Complex-Cyclosome, Statistics, Nonparametric, Neuronal Plasticity: physiology, Hippocampus: cytology, Bicuculline: pharmacology, Animals, Nonparametric, GABA-A Receptor Antagonists, Receptors, AMPA, Ubiquitin-Protein Ligase Complexes: genetics, Neurons: cytology, Analysis of Variance, Proteasome Endopeptidase Complex: metabolism, Down-Regulation: physiology, Excitatory Postsynaptic Potentials, AMPA: metabolism, EphA4: metabolism, Synapses, RNA, Ubiquitination: physiology, Proteasome Endopeptidase Complex: genetics, Synapses: drug effects, Ubiquitin-Protein Ligase Complexes: metabolism
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