Protein kinase A regulates calcium permeability of NMDA receptors

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.

[1]  O. Garaschuk,et al.  Fractional Ca2+ currents through somatic and dendritic glutamate receptor channels of rat hippocampal CA1 pyramidal neurones. , 1996, The Journal of physiology.

[2]  G. Fischbach,et al.  Calcium-dependent, slow desensitization distinguishes different types of glutamate receptors , 1989, Cellular and Molecular Neurobiology.

[3]  A. Konnerth,et al.  Fractional contribution of calcium to the cation current through glutamate receptor channels , 1993, Neuron.

[4]  M. Bear,et al.  LTP and LTD An Embarrassment of Riches , 2004, Neuron.

[5]  R. Carroll,et al.  NMDA-receptor trafficking and targeting: implications for synaptic transmission and plasticity , 2002, Trends in Neurosciences.

[6]  M. Mayer,et al.  Permeation and block of N‐methyl‐D‐aspartic acid receptor channels by divalent cations in mouse cultured central neurones. , 1987, The Journal of physiology.

[7]  K. Williams,et al.  Expression of mRNAs encoding subunits of the N-methyl-D-aspartate receptor in cultured cortical neurons. , 1994, Molecular pharmacology.

[8]  Louis J Muglia,et al.  Calcium-Stimulated Adenylyl Cyclase Activity Is Critical for Hippocampus-Dependent Long-Term Memory and Late Phase LTP , 1999, Neuron.

[9]  Alison L. Barth,et al.  A developmental switch in the signaling cascades for LTP induction , 2003, Nature Neuroscience.

[10]  S. Shenolikar,et al.  Gating of CaMKII by cAMP-regulated protein phosphatase activity during LTP. , 1998, Science.

[11]  J. A. Dani,et al.  Comparison of quantitative calcium flux through NMDA, ATP, and ACh receptor channels. , 1995, Biophysical journal.

[12]  C. Jahr,et al.  β-Adrenergic Regulation of Synaptic NMDA Receptors by cAMP-Dependent Protein Kinase , 1996, Neuron.

[13]  K. Gottmann,et al.  Synaptic Activity‐Dependent Developmental Regulation of NMDA Receptor Subunit Expression in Cultured Neocortical Neurons , 2000, Journal of neurochemistry.

[14]  B. Orser,et al.  Regulation of NMDA receptors in cultured hippocampal neurons by protein phosphatases 1 and 2A , 1994, Nature.

[15]  J. David Sweatt,et al.  Roles of serine/threonine phosphatases in hippocampel synaptic plasticity , 2001, Nature Reviews Neuroscience.

[16]  Christian Rosenmund,et al.  Inactivation of NMDA channels in cultured hippocampal neurons by intracellular calcium , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[17]  N. Daw,et al.  Cyclic AMP-dependent protein kinase mediates ocular dominance shifts in cat visual cortex , 2001, Nature Neuroscience.

[18]  I. C. Wiseman.  An Embarrassment of Riches or a Richness of Embarrassments. , 1984 .

[19]  M. Bennett,et al.  Protein kinase C modulates NMDA receptor trafficking and gating , 2001, Nature Neuroscience.

[20]  Richard L. Huganir,et al.  Postsynaptic organisation and regulation of excitatory synapses , 2000, Nature Reviews Neuroscience.

[21]  松崎 政紀.  Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons , 2001 .

[22]  S. Cull-Candy,et al.  Role of Distinct NMDA Receptor Subtypes at Central Synapses , 2004, Science's STKE.

[23]  Mark F. Bear,et al.  Rapid, experience-dependent expression of synaptic NMDA receptors in visual cortex in vivo , 1999, Nature Neuroscience.

[24]  E R Kandel,et al.  Impaired hippocampal plasticity in mice lacking the Cbeta1 catalytic subunit of cAMP-dependent protein kinase. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[25]  C. Lüscher,et al.  Restless AMPA receptors: implications for synaptic transmission and plasticity , 2001, Trends in Neurosciences.

[26]  J. Hell,et al.  Cyclic AMP-dependent Protein Kinase and Protein Kinase C Phosphorylate N-Methyl-d-aspartate Receptors at Different Sites* , 1997, The Journal of Biological Chemistry.

[27]  P. Greengard,et al.  The phosphoprotein DARPP-32 mediates cAMP-dependent potentiation of striatal N-methyl-D-aspartate responses. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[28]  S. Wang,et al.  Confocal imaging and local photolysis of caged compounds: Dual probes of synaptic function , 1995, Neuron.

[29]  R. Huganir,et al.  Characterization of Protein Kinase A and Protein Kinase C Phosphorylation of the N-Methyl-D-aspartate Receptor NR1 Subunit Using Phosphorylation Site-specific Antibodies* , 1997, The Journal of Biological Chemistry.

[30]  J. Lisman,et al.  Inhibition of the cAMP Pathway Decreases Early Long-Term Potentiation at CA1 Hippocampal Synapses , 2000, The Journal of Neuroscience.

[31]  Karel Svoboda,et al.  NMDA Receptor Subunit-Dependent [Ca2+] Signaling in Individual Hippocampal Dendritic Spines , 2005, The Journal of Neuroscience.

[32]  Rafael Yuste,et al.  A custom-made two-photon microscope and deconvolution system , 2000, Pflügers Archiv.

[33]  B Sakmann,et al.  Fractional calcium currents through recombinant GluR channels of the NMDA, AMPA and kainate receptor subtypes. , 1995, The Journal of physiology.

[34]  J. Lisman,et al.  D1/D5 Dopamine Receptor Activation Increases the Magnitude of Early Long-Term Potentiation at CA1 Hippocampal Synapses , 1996, The Journal of Neuroscience.

[35]  Robert C. Malenka,et al.  Postsynaptic factors control the duration of synaptic enhancement in area CA1 of the hippocampus , 1991, Neuron.

[36]  J. Ruppersberg.  Ion Channels in Excitable Membranes , 1996 .

[37]  CE Jahr,et al.  Synaptic desensitization of NMDA receptors by calcineurin , 1995, Science.

[38]  R. K. Simpson.  Nature Neuroscience , 2022 .

[39]  Mark Farrant,et al.  NMDA receptor subunits: diversity, development and disease , 2001, Current Opinion in Neurobiology.

[40]  C. Jahr,et al.  Beta-adrenergic regulation of synaptic NMDA receptors by cAMP-dependent protein kinase. , 1996, Neuron.

[41]  P. Greengard,et al.  A Dopamine/D1 Receptor/Protein Kinase A/Dopamine- and cAMP-Regulated Phosphoprotein (Mr 32 kDa)/Protein Phosphatase-1 Pathway Regulates Dephosphorylation of the NMDA Receptor , 1998, The Journal of Neuroscience.

[42]  M. Sheng,et al.  Molecular organization of the postsynaptic specialization , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[43]  E. Kandel,et al.  Recruitment of long-lasting and protein kinase A-dependent long-term potentiation in the CA1 region of hippocampus requires repeated tetanization. , 1994, Learning & memory.

[44]  M. Sheng,et al.  Regulation of NMDA receptors by an associated phosphatase-kinase signaling complex. , 1999, Science.

[45]  L. Kaczmarek,et al.  An early sodium and a late calcium phase in the afterdischarge of peptide-secreting neurons ofAplysia , 1982, Brain Research.

[46]  E. Kandel,et al.  Genetic Demonstration of a Role for PKA in the Late Phase of LTP and in Hippocampus-Based Long-Term Memory , 1997, Cell.

[47]  D C Spray,et al.  Intercellular Communication in Spinal Cord Astrocytes: Fine Tuning between Gap Junctions and P2 Nucleotide Receptors in Calcium Wave Propagation , 2000, The Journal of Neuroscience.

[48]  R. Schneggenburger,et al.  Simultaneous measurement of Ca2+ influx and reversal potentials in recombinant N-methyl-D-aspartate receptor channels. , 1996, Biophysical journal.

[49]  I. Módy,et al.  Regulation of NMDA channel function by endogenous Ca2+-dependent phosphatase , 1994, Nature.

[50]  W. Denk,et al.  Dendritic spines as basic functional units of neuronal integration , 1995, Nature.

[51]  R. Nicoll,et al.  Ca2+ Signaling Requirements for Long-Term Depression in the Hippocampus , 1996, Neuron.

[52]  W. Denk,et al.  Mechanisms of Calcium Influx into Hippocampal Spines: Heterogeneity among Spines, Coincidence Detection by NMDA Receptors, and Optical Quantal Analysis , 1999, The Journal of Neuroscience.

[53]  Mark J. Thomas,et al.  Activity-Dependent β-Adrenergic Modulation of Low Frequency Stimulation Induced LTP in the Hippocampal CA1 Region , 1996, Neuron.

[54]  M. Bennett,et al.  Postsynaptic Density Protein-95 Regulates NMDA Channel Gating and Surface Expression , 2004, The Journal of Neuroscience.