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Previous Article | Next Article
The Journal of Neuroscience, August 15, 2002, 22(16):7027-7044
Regulation of A-Kinase Anchoring Protein 79/150-cAMP-Dependent Protein Kinase Postsynaptic Targeting by NMDA Receptor Activation of Calcineurin and Remodeling of Dendritic Actin
Lisa. L. Gomez1, Shuvo Alam1, Karen E. Smith1, Eric Horne1, and Mark L. Dell'Acqua1, 2 1 Department of Pharmacology, 2 Program in Neuroscience, University of Colorado Health Sciences Center, Denver, Colorado 80262
At the postsynaptic membrane of glutamatergic synapses, the cAMP-dependent protein kinase (PKA), protein kinase C (PKC), and calcineurin (CaN) anchoring protein AKAP79/150 is recruited to NMDA and AMPA glutamate receptors by postsynaptic density (PSD)-95 family membrane-associated guanylate kinase (MAGUK) scaffold proteins. These signaling scaffold complexes may function to regulate receptor phosphorylation in synaptic plasticity. Thus, it is important to understand regulation of AKAP79/150 targeting to synapses and recruitment to PSD-MAGUK complexes. AKAP79 is targeted to the plasma membrane by an N-terminal basic domain that binds phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) and is regulated by PKC phosphorylation and calmodulin binding. Here we demonstrate that this same domain also binds F-actin in a calmodulin- and PKC-regulated manner, targets to membrane ruffles enriched in F-actin and PI-4,5-P2 in COS7 cells, and localizes to dendritic spines with F-actin and PSD-MAGUKs in hippocampal neurons. Inhibition of actin polymerization disrupted AKAP79 targeting of PKA and CaN to ruffles in COS7 cells and endogenous AKAP79/150 dendritic spine localization with PKA, CaN, and PSD-MAGUKs in neurons. AKAP79/150 postsynaptic localization was rapidly regulated by NMDA receptors through CaN activation and F-actin remodeling, further suggesting that AKAP79/150 signaling scaffold targeting depends on actin dynamics. NMDA receptor activation also regulated dendritic spine localization of PKA and CaN and association of the AKAP79/150-PKA complex with PSD-MAGUKs. Because AMPA receptor PKA phosphorylation and synaptic localization are regulated by similar NMDA receptor-CaN signaling pathways linked to hippocampal long-term depression, this regulation of AKAP79/150 postsynaptic targeting might be important for synaptic plasticity.
Key words: postsynaptic density; actin; PSD-95 MAGUKs; AKAPs; PKA; calcineurin; NMDA and AMPA receptors
Copyright © 2002 Society for Neuroscience 0270-6474/02/22167027-18$05.00/0
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