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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
Open accessAbstract
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-P(2)) 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-P(2) 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.
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“AKAP79/150 is targeted to dendritic spines and the PSD by an N-terminal basic region that is palmitoylated on two Cys residues and binds directly to the membrane lipid phosphatidylinositol-4,5-bisphosphate (PIP2), the actin cytoskeleton, and cadherin adhesion molecules”
From AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca2+-Permeable AMPA Receptors (2012) · cites this paper as Gomez et al., 2002
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“This AKAP removal from synapses is caused by inhibition of N-terminal targeting interactions through depalmitoylation, phospholipase C cleavage of PIP2, and CaN-dependent actin depolymerization”
From AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca2+-Permeable AMPA Receptors (2012) · cites this paper as Gomez et al., 2002
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“LTD leads to loss of AKAP79/150 binding to PSD-95 and cadherins and removal of the AKAP and PKA from synapses”
From AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca2+-Permeable AMPA Receptors (2012) · cites this paper as Gomez et al., 2002
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“CaN activity is also required for cLTD-induced F-actin depolymerization and subsequent disruption of AKAP150 binding to PSD-95 and membranes (Gomez et al., 2002); this uncoupling of AKAP150 from PSD-95 and membranes may prevent PKA re-phosphorylation of GluA1 that would promote recycling after LTD”
From AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca2+-Permeable AMPA Receptors (2012) · cites this paper as Gomez et al., 2002
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Malenka, R. C., & Bear, M. F. (2004) · Neuron · doi:10.1016/j.neuron.2004.09.012 · Cited by 3,968
Synaptic Plasticity: Multiple Forms, Functions, and Mechanisms
Citri, A., & Malenka, R. C. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301559 · Cited by 2,323
Localized Effects of cAMP Mediated by Distinct Routes of Protein Kinase A
Taskén, K., & Aandahl, E. M. (2004) · Physiological Reviews · doi:10.1152/physrev.00021.2003 · Cited by 807
Fukazawa, Y., Saitoh, Y., Ozawa, F., Ohta, Y., Mizuno, K., & Inokuchi, K. (2003) · Neuron · doi:10.1016/s0896-6273(03)00206-x · Cited by 695
Peng, J., Kim, M. J., Cheng, D., Duong, D. M., Gygi, S. P., & Sheng, M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m400103200 · Cited by 473
Metadata
- Authors
- Gomez, L. L., Alam, S., Smith, K. E., Horne, E., & Dell'Acqua, M. L.
- ORCID
- Horne, Eric
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2002-08-15
- Volume
- 22
- Issue
- 16
- Pages
- 7027-7044
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6757891
- OpenAlex
- W2101875004
- Cited by
- 170
- References
- 68
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 7 · 2017: 5 · 2016: 5 · 2015: 8 · 2014: 11 · 2013: 8 · 2012: 11
- FWCI
- 4.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health (NS40701)
- National Institute of Neurological Disorders and Stroke (R56NS040701, R01NS040701)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- AKAP79/150, protein kinase A, calcineurin, NMDA receptor signaling, F-actin binding, phosphatidylinositol 4,5-bisphosphate, calmodulin, protein kinase C, dendritic spines, ruffles, synaptic plasticity, hippocampal neurons, AMPA receptor phosphorylation
- MeSH terms
- Disks Large Homolog 4 Protein, Actins, Animals, Carrier Proteins, Cells, Cultured, Dendrites, Membrane Proteins, Nerve Tissue Proteins, Neurons, Peptide Fragments, Protein Binding, Synapses, Transfection, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Protein Structure, Tertiary, Cyclic AMP-Dependent Protein Kinases, Receptors, AMPA, COS Cells, Calcineurin, Protein Transport, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Rats, A Kinase Anchor Proteins
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