Nature Neuroscience 9, 501 - 510 (2006)
Published online: 12 March 2006; | doi:10.1038/nn1664
Protein kinase A regulates calcium permeability of NMDA receptorsV Arvydas Skeberdis1, 3, 4, Vivien Chevaleyre1, 4, C Geoffrey Lau1, 4, Jesse H Goldberg2, 3, Diana L Pettit1, Sylvia O Suadicani1, Ying Lin1, Michael V L Bennett1, Rafael Yuste2, Pablo E Castillo1
& R Suzanne Zukin11
Rose F. Kennedy Center for Research in Mental Retardation and Developmental Disabilities, Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA. 2
Howard Hughes Medical Institute, Department of Biological Sciences, Columbia University, New York, New York 10027, USA. 3
Present addresses: Institute of Cardiology, Kaunas University of Medicine, 3007 Kaunas, Lithuania (V.A.S.) and McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA (J.H.G.). 4
These authors contributed equally to this work.
Correspondence should be addressed to R Suzanne Zukin zukin@aecom.yu.edu 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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