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Cited by 170Neuroscience and Neuropharmacology ResearchProtein Kinase Regulation and GTPase SignalingSignaling Pathways in Disease

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

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Gomez, Lisa. L., Alam, Shuvo, Smith, Karen E., Horne, Eric, Dell'Acqua, Mark L.·2002·The Journal of Neuroscience
DOI 10.1523/jneurosci.22-16-07027.2002PMC PMC6757891
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Abstract

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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Crossref · 10.1523/jneurosci.22-16-07027.2002

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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 PIP2, the actin cytoskeleton, and cadherin adhesion molecules.

    “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 Ca<sup>2+</sup>-Permeable AMPA Receptors (2012) · cites this paper as Gomez et al., 2002

    The Results section reports that the AKAP79 N-terminal basic domain targets dendritic spines and binds F-actin; it also identifies PI-4,5-P2-binding basic regions. The same section attributes palmitoylation sites to PSD-95, not AKAP79, and the passages do not support binding to cadherin adhesion molecules. No page numbers are available in our copy. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • 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.

    “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 Ca<sup>2+</sup>-Permeable AMPA Receptors (2012) · cites this paper as Gomez et al., 2002

    The section on reorganization of dendritic spine F-actin reports that CaN-associated actin remodeling is likely to untether AKAP79/150 from the postsynaptic cytoskeleton, and that stabilizing F-actin prevents its NMDA-mediated redistribution. The section on the AKAP79 N-terminal basic domain describes binding to PI-4,5-P2, but does not show that depalmitoylation or phospholipase C cleavage of PIP2 causes AKAP removal. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • LTD leads to loss of AKAP79/150 binding to PSD-95 and cadherins and removal of the AKAP and PKA from synapses.

    “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 Ca<sup>2+</sup>-Permeable AMPA Receptors (2012) · cites this paper as Gomez et al., 2002

    The section on AKAP79/150–PKA association with PSD-MAGUKs reports that NMDA treatment disrupts those complexes, while the section on pathways shared with LTD describes NMDA-triggered removal of the AKAP79/150–PKA complex from synapses. The paper connects these findings to LTD-related signaling, but does not show that LTD itself causes them; the passages do not establish loss of binding to cadherins. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • CaN activity is required for cLTD-induced F-actin depolymerization and subsequent disruption of AKAP150 binding to PSD-95 and membranes; this uncoupling may prevent PKA re-phosphorylation of GluA1 that would promote recycling after LTD.

    “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 Ca<sup>2+</sup>-Permeable AMPA Receptors (2012) · cites this paper as Gomez et al., 2002

    In ‘Activation of the phosphatase calcineurin but not protein kinases is necessary for NMDA receptor regulation of AKAP79/150 targeting’ (page unavailable), calcineurin inhibitors mostly prevented NMDA-induced AKAP79/150 redistribution. The F-actin results and the ‘pathways shared with LTD’ discussion (pages unavailable) support a proposed sequence of actin remodeling, loss of association with PSD-95, and membrane release. The paper studied glutamate/NMDA-treated neurons rather than directly demonstrating this sequence during cLTD; the GluA1 recycling proposal follows the citation and is not attributed to this source. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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2 of the 68 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Goslin K, Asmussen H, Banker G (1998) Rat hippocampal neurons in low density culture In: Culturing nerve cells, Ed 2 (Banker G, Goslin K, eds), pp 339 -370. Cambridge, MA: MIT.

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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
DOI
10.1523/jneurosci.22-16-07027.2002
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
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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