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Protein kinase A regulates calcium permeability of NMDA receptors

Nature Neuroscience volume 9, pages 501–510 (2006)Cite this article

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 Ca2+ 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.

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Figure 1: PKA modulates NMDA-elicited currents and Ca2+-dependent desensitization in hippocampal neurons.
Figure 2: PKA modulates Ca2+ and Ba2+ permeation through NMDA channels.
Figure 3: PKA modulates Ca2+ influx through NMDARs.
Figure 4: PKA differentially regulates NR2A versus NR2B receptor–mediated currents.
Figure 5: PKA selectively regulates synaptically induced Ca2+ rises in dendritic spines.
Figure 6: LTP induction is reduced after blocking PKA but can be rescued by increasing extracellular Ca2+ concentration during the tetanus.

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Acknowledgements

The authors thank K. Svoboda for helpful scientific discussions, G. Bassell for neuronal cultures, G. Hjelmstad for the IgorPro procedures for data acquisition and L. Formisano for technical assistance. This work was supported by the US National Institutes of Health (grants NS20752 to R.S.Z., DA17392 to P.E.C., MH65495 supporting S.O.S. and NS45287 to M.V.L.B.). P.E.C. is a Pew Biomedical Scholar. M.V.L.B. is the Sylvia and Robert S. Olnick Professor of Neuroscience and Distinguished Professor at the Albert Einstein College of Medicine.

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Author notes

  1. V Arvydas Skeberdis

    Present address: Institute of Cardiology, Kaunas University of Medicine, 3007, Kaunas, Lithuania

  2. Jesse H Goldberg

    Present address: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA

  3. V Arvydas Skeberdis, Vivien Chevaleyre and C Geoffrey Lau: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroscience, Rose F. Kennedy Center for Research in Mental Retardation and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, 10461, New York, USA

    V Arvydas Skeberdis, Vivien Chevaleyre, C Geoffrey Lau, Diana L Pettit, Sylvia O Suadicani, Ying Lin, Michael V L Bennett, Pablo E Castillo & R Suzanne Zukin

  2. Department of Biological Sciences, Howard Hughes Medical Institute, Columbia University, New York, 10027, New York, USA

    Jesse H Goldberg & Rafael Yuste

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Supplementary information

Supplementary Fig. 1

PKA inhibitors and activators do not alter NMDA-elicited currents in Xenopus oocytes expressing recombinant NMDARs. (PDF 159 kb)

Supplementary Fig. 2

PKA does not modulate NMDAR surface expression in cortical neurons. (PDF 103 kb)

Supplementary Fig. 3

PKA inhibitors and activators modulate Ca2+ influx through NMDARs. (PDF 97 kb)

Supplementary Fig. 4

PKA does not act presynaptically to inhibit LTP at the Schaffer collateral-CA1 synapse. (PDF 102 kb)

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Skeberdis, V., Chevaleyre, V., Lau, C. et al. Protein kinase A regulates calcium permeability of NMDA receptors. Nat Neurosci 9, 501–510 (2006). https://doi.org/10.1038/nn1664

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