Protein kinase A regulates calcium permeability of NMDA receptors

V. Arvydas Skeberdis, Vivien Chevaleyre, C. Geoffrey Lau, Jesse H. Goldberg, Diana L. Pettit, Sylvia O. Suadicani, Ying Lin, Michael V.L. Bennett, Rafael Yuste, Pablo E. Castillo, R. Suzanne Zukin

Research output: Contribution to journalArticle

218 Scopus citations

Abstract

Calcium (Ca2+) influx through NMDA receptors (NMDARs) is essential for synaptogenesis, experience-dependent synaptic remodeling and plasticity. The NMDAR-mediated rise in postsynaptic Ca2+ activates a network of kinases and phosphatases that promote persistent changes in synaptic strength, such as long-term potentiation (LTP). Here we show that the Ca 2+ permeability of neuronal NMDARs is under the control of the cyclic AMP-protein kinase A (cAMP-PKA) signaling cascade. PKA blockers reduced the relative fractional Ca2+ influx through NMDARs as determined by reversal potential shift analysis and by a combination of electrical recording and Ca2+ influx measurements in rat hippocampal neurons in culture and hippocampal slices from mice. In slices, PKA blockers markedly inhibited NMDAR-mediated Ca2+ rises in activated dendritic spines, with no significant effect on synaptic current. Consistent with this, PKA blockers depressed the early phase of NMDAR-dependent LTP at hippocampal Schaffer collateral-CA1 (Sch-CA1) synapses. Our data link PKA-dependent synaptic plasticity to Ca2+ signaling in spines and thus provide a new mechanism whereby PKA regulates the induction of LTP.

Original languageEnglish (US)
Pages (from-to)501-510
Number of pages10
JournalNature Neuroscience
Volume9
Issue number4
DOIs
StatePublished - Apr 1 2006

ASJC Scopus subject areas

  • Neuroscience(all)

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    Skeberdis, V. A., Chevaleyre, V., Lau, C. G., Goldberg, J. H., Pettit, D. L., Suadicani, S. O., Lin, Y., Bennett, M. V. L., Yuste, R., Castillo, P. E., & Zukin, R. S. (2006). Protein kinase A regulates calcium permeability of NMDA receptors. Nature Neuroscience, 9(4), 501-510. https://doi.org/10.1038/nn1664