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

doi:10.1038/nn1664

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 journal › Article › peer-review

250 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 language	English (US)
Pages (from-to)	501-510
Number of pages	10
Journal	Nature Neuroscience
Volume	9
Issue number	4
DOIs	https://doi.org/10.1038/nn1664
State	Published - Apr 2006

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Neuroscience(all)

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@article{052f9c0ca35b4d969535a241ce44f9d9,

title = "Protein kinase A regulates calcium permeability of NMDA receptors",

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.",

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

note = "Funding Information: 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.",

year = "2006",

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doi = "10.1038/nn1664",

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T1 - Protein kinase A regulates calcium permeability of NMDA receptors

AU - Skeberdis, V. Arvydas

AU - Chevaleyre, Vivien

AU - Lau, C. Geoffrey

AU - Goldberg, Jesse H.

AU - Pettit, Diana L.

AU - Suadicani, Sylvia O.

AU - Lin, Ying

AU - Bennett, Michael V.L.

AU - Yuste, Rafael

AU - Castillo, Pablo E.

AU - Zukin, R. Suzanne

N1 - Funding Information: 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.

PY - 2006/4

Y1 - 2006/4

N2 - 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.

AB - 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.

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DO - 10.1038/nn1664

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JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 4

ER -

Protein kinase A regulates calcium permeability of NMDA receptors

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