Regulation of GluR1 by the A-kinase anchoring protein 79 (AKAP79) signaling complex shares properties with long-term depression
Open accessAbstract
Second messengers regulate synaptic plasticity by influencing the balance between kinase and phosphatase activity. One target of this balance is the phosphorylation state of the AMPA receptor glutamate receptor 1 (GluR1) subunit. Hippocampal long-term depression (LTD) is a calcium-dependent downregulation of synaptic AMPA receptor currents associated with dephosphorylation of Ser845, a cAMP-dependent protein kinase (PKA) site on GluR1. Recruitment of kinases and phosphatases to the AMPA receptor might enable modulation of AMPA receptor function. The neuronal A-kinase anchoring protein AKAP79/150 interacts with PKA and the calcium-dependent protein phosphatase PP2B and is linked to the AMPA receptor GluR1 subunit by synapse-associated protein 97 (SAP97), a membrane-associated guanylate kinase family protein. Here we demonstrate that AKAP79 not only promotes basal phosphorylation of Ser845 but also confers a calcium- and PP2B-mediated downregulation to GluR1 receptor currents. This AKAP79-dependent downregulation is contingent on the local presence of PKA, Ser845 of GluR1, and a PDZ (postsynaptic density 95/Discs large/zona occludens 1)-domain interaction between GluR1 and SAP97, all of which support basal phosphorylation of the receptor. These findings suggest that the AKAP79 signaling complex is sufficient to couple intracellular calcium levels to the PKA phosphorylation state of GluR1. Thus, the integration of intracellular signals relevant for LTD may be transduced to GluR1 by the AKAP79 signaling complex.
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In cultured rat hippocampal neurons, Ca2+, CaN activity, and the AKAP79/150 CaN anchoring domain are required for down-regulation of AMPAR currents and internalization of AMPAR in response to acute NMDA receptor activation or inhibition of PKA anchoring and activity.
“In cultured rat hippocampal neurons, Ca2+, CaN activity, and the AKAP79/150 CaN anchoring domain are required for the down-regulation of AMPAR currents and internalization of AMPAR in response to either acute NMDA receptor activation or inhibition of PKA anchoring and activity”
From AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca<sup>2+</sup>-Permeable AMPA Receptors (2012) · cites this paper as Tavalin et al., 2002
The Results section reports that disrupting PKA anchoring reduced AMPA receptor currents in cultured hippocampal neurons, and that removing extracellular calcium or inhibiting PP2B prevented this rundown. It does not establish that the AKAP79/150 PP2B-anchoring domain is required in those neurons, or show AMPA receptor internalization. NMDA receptors were blocked during the current recordings, rather than acutely activated. Page numbers are unavailable in our copy. (LLM, conf=0.89)
Experimental — accuracy not yet measuredThe findings are in agreement with previous studies in culture preparations that implicated AKAP79/150-CaN anchoring in regulation of AMPAR activity and endocytosis underlying LTD.
“Our findings are also in agreement with previous studies in culture preparations that implicated AKAP79/150-CaN anchoring in regulation of AMPAR activity and endocytosis underlying 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 Tavalin et al., 2002
The Results report that disrupting kinase anchoring reduced AMPA receptor currents in cultured hippocampal neurons, and the Discussion links AKAP79/150-anchored PP2B regulation to properties of LTD. The Discussion discusses AMPA receptor endocytosis as a possible related mechanism, but does not establish that AKAP79/150–PP2B anchoring regulates endocytosis underlying LTD. No page numbers are available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPeptide-mediated inhibition of PKA anchoring or activity caused a very similar decrease in AMPAR currents in hippocampal neurons that was mediated by CaN activation in part by Ca2+ influx through Ca2+-permeable AMPARs.
“peptide-mediated inhibition of PKA anchoring or activity caused a very similar decrease in AMPAR currents in hippocampal neurons that was mediated by CaN activation in part by Ca2+ influx through Ca2+-permeable AMPARs”
From AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca<sup>2+</sup>-Permeable AMPA Receptors (2012) · cites this paper as Tavalin et al., 2002
In “Results: PP2B underlies rundown of hippocampal AMPA receptor current” (page unavailable), the Ht31 peptide disrupts PKA anchoring and reduces currents in cultured hippocampal neurons; cyclosporin A prevents that rundown. The authors suggest that calcium entry through calcium-permeable AMPA receptors may contribute to its initial phase. The passage describing peptide inhibition of PKA activity with PKI concerns reconstituted receptors in HEK293 cells, not hippocampal neurons, so the claim extends that part of the finding to a different cell type. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPast work in heterologous cells demonstrated that negative regulation of recombinant GluA1 currents by AKAP79 involved dephosphorylation of S845 but not S831, required anchored CaN, and was opposed by anchored PKA.
“past work in heterologous cells demonstrated that negative regulation of recombinant GluA1 currents by AKAP79 involved dephosphorylation of S845 but not S831, required anchored CaN, and was opposed by anchored PKA”
From AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca<sup>2+</sup>-Permeable AMPA Receptors (2012) · cites this paper as Tavalin et al., 2002
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- Authors
- Tavalin, S. J., Colledge, M., Hell, J. W., Langeberg, L. K., Huganir, R. L., & Scott, J. D.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Iowa (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2002-04-15
- Volume
- 22
- Issue
- 8
- Pages
- 3044-3051
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6757527
- OpenAlex
- W2130907973
- Cited by
- 222
- References
- 4
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 6 · 2021: 4 · 2020: 4 · 2019: 6 · 2018: 3 · 2017: 8 · 2016: 6 · 2015: 6 · 2014: 7 · 2013: 10 · 2012: 11
- FWCI
- 6.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council Canada
- National Institutes of Health (HEK293)
- Medical Research Council
- National Institute of Neurological Disorders and Stroke (F32NS010202, R01NS035563)
- 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
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- AKAP79, GluR1, AMPA receptors, long-term depression, protein kinase A, calcineurin, SAP97, PDZ domain, calcium signaling, synaptic plasticity, hippocampus, receptor dephosphorylation, signaling complexes
- MeSH terms
- Animals, Binding Sites, Calcium, Carrier Proteins, Cells, Cultured, Kidney, Membrane Proteins, Nerve Tissue Proteins, Neural Inhibition, Neuronal Plasticity, Neurons, Phosphorylation, Precipitin Tests, Protein Binding, Time, Second Messenger Systems, Signal Transduction, Rats, Sprague-Dawley, Cyclic AMP-Dependent Protein Kinases, Receptors, AMPA, Patch-Clamp Techniques, Glutamic Acid, Calcineurin, Macromolecular Substances, Adaptor Proteins, Signal Transducing, Rats, A Kinase Anchor Proteins
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