AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca2+-Permeable AMPA Receptors
| Autor: | Emily S. Gibson, Jennifer L. Sanderson, Jessica A. Gorski, Ronald K. Freund, Mark L. Dell'Acqua, Philip Lam, Wallace S. Chick |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Patch-Clamp Techniques A Kinase Anchor Proteins Action Potentials Hippocampus Mice Excitatory Amino Acid Agonists Serine Phosphorylation Long-term depression Cells Cultured Neurons Neuronal Plasticity Synaptic scaling Calcineurin musculoskeletal neural and ocular physiology General Neuroscience Long-term potentiation Cell biology Female Disks Large Homolog 4 Protein Synaptic tagging Sodium Channel Blockers Subcellular Fractions Silver Staining N-Methylaspartate Dendritic Spines Biophysics Mice Transgenic Tetrodotoxin AMPA receptor In Vitro Techniques Biology Article Quinoxalines Synaptic augmentation Animals Immunoprecipitation Receptors AMPA Analysis of Variance Excitatory Postsynaptic Potentials Membrane Proteins Electric Stimulation Mice Inbred C57BL Synaptic fatigue nervous system Mutation Synapses Synaptic plasticity Calcium Excitatory Amino Acid Antagonists Guanylate Kinases |
| Zdroj: | The Journal of Neuroscience. 32:15036-15052 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.3326-12.2012 |
| Popis: | AMPA receptors (AMPARs) are tetrameric ion channels assembled from GluA1–GluA4 subunits that mediate the majority of fast excitatory synaptic transmission in the brain. In the hippocampus, most synaptic AMPARs are composed of GluA1/2 or GluA2/3 with the GluA2 subunit preventing Ca2+influx. However, a small number of Ca2+-permeable GluA1 homomeric receptors reside in extrasynaptic locations where they can be rapidly recruited to synapses during synaptic plasticity. Phosphorylation of GluA1 S845 by the cAMP-dependent protein kinase (PKA) primes extrasynaptic receptors for synaptic insertion in response to NMDA receptor Ca2+signaling during long-term potentiation (LTP), while phosphatases dephosphorylate S845 and remove synaptic and extrasynaptic GluA1 during long-term depression (LTD). PKA and the Ca2+-activated phosphatase calcineurin (CaN) are targeted to GluA1 through binding to A-kinase anchoring protein 150 (AKAP150) in a complex with PSD-95, but we do not understand how the opposing activities of these enzymes are balanced to control plasticity. Here, we generated AKAP150ΔPIX knock-in mice to selectively disrupt CaN anchoringin vivo. We found that AKAP150ΔPIX mice lack LTD but express enhanced LTP at CA1 synapses. Accordingly, basal GluA1 S845 phosphorylation is elevated in AKAP150ΔPIX hippocampus, and LTD-induced dephosphorylation and removal of GluA1, AKAP150, and PSD-95 from synapses are impaired. In addition, basal synaptic activity of GluA2-lacking AMPARs is increased in AKAP150ΔPIX mice and pharmacologic antagonism of these receptors restores normal LTD and inhibits the enhanced LTP. Thus, AKAP150-anchored CaN opposes PKA phosphorylation of GluA1 to restrict synaptic incorporation of Ca2+-permeable AMPARs both basally and during LTP and LTD. |
| Databáze: | OpenAIRE |
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