Regulation of Synaptic Strength by Protein Phosphatase 1

We investigated the role of postsynaptic protein phosphatase 1 (PP1) in regulating synaptic strength by loading CA1 pyramidal cells either with peptides that disrupt PP1 binding to synaptic targeting proteins or with active PP1. The peptides blocked synaptically evoked LTD but had no effect on basal synaptic currents mediated by either AMPA or NMDA receptors. They did, however, cause an increase in synaptic strength following the induction of LTD. Similarly, PP1 had no effect on basal synaptic strength but enhanced LTD. In cultured neurons, synaptic activation of NMDA receptors increased the proportion of PP1 localized to synapses. These results suggest that PP1 does not significantly regulate basal synaptic strength. Appropriate NMDA receptor activation, however, allows PP1 to gain access to synaptic substrates and be recruited to synapses where its activity is necessary for sustaining LTD.

[1]  A. Crisanti,et al.  Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity , 2022 .

[2]  M. Bear,et al.  Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. , 2000, Science.

[3]  Philip R. Cohen,et al.  The major myosin phosphatase in skeletal muscle is a complex between the β‐isoform of protein phosphatase 1 and the MYPT2 gene product , 1998, FEBS letters.

[4]  S. Endo,et al.  Multiple structural elements define the specificity of recombinant human inhibitor-1 as a protein phosphatase-1 inhibitor. , 1996, Biochemistry.

[5]  E Thiels,et al.  Transient and persistent increases in protein phosphatase activity during long-term depression in the adult hippocampus in vivo , 1998, Neuroscience.

[6]  J. H. Connor,et al.  Molecular memory by reversible translocation of calcium/calmodulin-dependent protein kinase II , 2000, Nature Neuroscience.

[7]  Robert C. Malenka,et al.  Independent mechanisms for long-term depression of AMPA and NMDA responses , 1995, Neuron.

[8]  P. Greengard,et al.  Spinophilin regulates the formation and function of dendritic spines. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[9]  J. Hell,et al.  Calcium/calmodulin-dependent protein kinase II is associated with the N-methyl-D-aspartate receptor. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[10]  P. Greengard,et al.  Regulation of neurabin I interaction with protein phosphatase 1 by phosphorylation. , 1999, Biochemistry.

[11]  G. R. Seabrook,et al.  The group I mGlu receptor agonist DHPG induces a novel form of LTD in the CA1 region of the hippocampus , 1997, Neuropharmacology.

[12]  Yu Tian Wang,et al.  Regulation of AMPA Receptor–Mediated Synaptic Transmission by Clathrin-Dependent Receptor Internalization , 2000, Neuron.

[13]  P. De Koninck,et al.  Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations. , 1998, Science.

[14]  R. Nicoll,et al.  Long-term potentiation--a decade of progress? , 1999, Science.

[15]  R. Malenka,et al.  An essential role for protein phosphatases in hippocampal long-term depression. , 1993, Science.

[16]  A. deGuzman,et al.  Preparation of low-molecular-weight forms of rabbit muscle protein phosphatase. , 1988, Methods in enzymology.

[17]  Andreas Lüthi,et al.  Hippocampal LTD Expression Involves a Pool of AMPARs Regulated by the NSF–GluR2 Interaction , 1999, Neuron.

[18]  D. Linden,et al.  Long-term synaptic depression in the mammalian brain , 1994, Neuron.

[19]  T. Soderling,et al.  Ca2+/calmodulin-kinase II enhances channel conductance of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[20]  J. Lisman,et al.  A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[21]  E. Kandel,et al.  Low-frequency stimulation erases LTP through an NMDA receptor-mediated activation of protein phosphatases. , 1994, Learning & memory.

[22]  K. Shen,et al.  Dynamic control of CaMKII translocation and localization in hippocampal neurons by NMDA receptor stimulation. , 1999, Science.

[23]  R. Huganir,et al.  Phosphorylation of the AMPA Receptor Subunit GluR2 Differentially Regulates Its Interaction with PDZ Domain-Containing Proteins , 2000, The Journal of Neuroscience.

[24]  R. Nicoll,et al.  Two Distinct Forms of Long-Term Depression Coexist in CA1 Hippocampal Pyramidal Cells , 1997, Neuron.

[25]  P. Greengard,et al.  Spinophilin, a novel protein phosphatase 1 binding protein localized to dendritic spines. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[26]  M. Bollen,et al.  Combinatorial control of protein phosphatase-1. , 2001, Trends in biochemical sciences.

[27]  M. Ehlers,et al.  Reinsertion or Degradation of AMPA Receptors Determined by Activity-Dependent Endocytic Sorting , 2000, Neuron.

[28]  I. Fraser,et al.  Modulation of Ion Channels A “Current” View of AKAPs , 1999, Neuron.

[29]  Paul De Koninck,et al.  Interaction with the NMDA receptor locks CaMKII in an active conformation , 2001, Nature.

[30]  S. Shenolikar,et al.  Physiologic importance of protein phosphatase inhibitors. , 1998, Frontiers in bioscience : a journal and virtual library.

[31]  J. Isaac,et al.  Evidence for silent synapses: Implications for the expression of LTP , 1995, Neuron.

[32]  T. Teyler,et al.  Long-term potentiation. , 1987, Annual review of neuroscience.

[33]  P. Greengard,et al.  Protein phosphatase 1 modulation of neostriatal AMPA channels: regulation by DARPP–32 and spinophilin , 1999, Nature Neuroscience.

[34]  M. Mumby,et al.  Brain protein serine/threonine phosphatases , 1999, Current Opinion in Neurobiology.

[35]  Mark F Bear,et al.  Involvement of a Postsynaptic Protein Kinase A Substrate in the Expression of Homosynaptic Long-Term Depression , 1998, Neuron.

[36]  P. De Camilli,et al.  The Calcineurin-Dynamin 1 Complex as a Calcium Sensor for Synaptic Vesicle Endocytosis* , 1999, The Journal of Biological Chemistry.

[37]  T. Soderling,et al.  Postsynaptic protein phosphorylation and LTP , 2000, Trends in Neurosciences.

[38]  M. Bear,et al.  Metaplasticity: the plasticity of synaptic plasticity , 1996, Trends in Neurosciences.

[39]  W. Catterall,et al.  Voltage-dependent potentiation of L-type Ca2+ channels in skeletal muscle cells requires anchored cAMP-dependent protein kinase. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[40]  Mark von Zastrow,et al.  Rapid redistribution of glutamate receptors contributes to long-term depression in hippocampal cultures , 1999, Nature Neuroscience.

[41]  W. Catterall,et al.  Voltage-dependent potentiation of L-type Ca2+ channels due to phosphorylation by cAMP-dependent protein kinase , 1993, Nature.

[42]  M. Tamura,et al.  Brain Actin-associated Protein Phosphatase 1 Holoenzymes Containing Spinophilin, Neurabin, and Selected Catalytic Subunit Isoforms* , 1999, The Journal of Biological Chemistry.

[43]  R. Huganir,et al.  Targeting of PKA to Glutamate Receptors through a MAGUK-AKAP Complex , 2000, Neuron.

[44]  R. Huganir,et al.  Control of GluR1 AMPA Receptor Function by cAMP-Dependent Protein Kinase , 2000, The Journal of Neuroscience.

[45]  D. Brautigan,et al.  Glycogen Synthase Association with the Striated Muscle Glycogen-targeting Subunit of Protein Phosphatase-1 , 2000, The Journal of Biological Chemistry.

[46]  P. Cohen,et al.  On target with a new mechanism for the regulation of protein phosphorylation. , 1993, Trends in biochemical sciences.

[47]  Andreas Lüthi,et al.  Modulation of AMPA receptor unitary conductance by synaptic activity , 1998, Nature.

[48]  Mark F Bear,et al.  NMDA Induces Long-Term Synaptic Depression and Dephosphorylation of the GluR1 Subunit of AMPA Receptors in Hippocampus , 1998, Neuron.

[49]  S. Shenolikar,et al.  Neurofilament-L Is a Protein Phosphatase-1-binding Protein Associated with Neuronal Plasma Membrane and Post-synaptic Density* , 2000, The Journal of Biological Chemistry.

[50]  M. Bear,et al.  Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity , 2000, Nature.

[51]  Mark von Zastrow,et al.  Role of ampa receptor endocytosis in synaptic plasticity , 2001, Nature Reviews Neuroscience.

[52]  R. Nicoll,et al.  NMDA-receptor-dependent synaptic plasticity: multiple forms and mechanisms , 1993, Trends in Neurosciences.

[53]  Mark von Zastrow,et al.  Role of AMPA Receptor Cycling in Synaptic Transmission and Plasticity , 1999, Neuron.

[54]  M. H. Cobb,et al.  Dual MAP kinase pathways mediate opposing forms of long-term plasticity at CA3–CA1 synapses , 2000, Nature Neuroscience.

[55]  T Watanabe,et al.  Characterization of the neuronal targeting protein spinophilin and its interactions with protein phosphatase-1. , 1999, Biochemistry.

[56]  Jie Yang,et al.  Cellular Mechanisms Regulating Protein Phosphatase-1 , 2000, The Journal of Biological Chemistry.

[57]  S. Shenolikar,et al.  Mutations of the serine phosphorylated in the protein phosphatase-1-binding motif in the skeletal muscle glycogen-targeting subunit. , 2000, The Biochemical journal.

[58]  R. Malenka,et al.  Involvement of a calcineurin/ inhibitor-1 phosphatase cascade in hippocampal long-term depression , 1994, Nature.

[59]  S Matsuda,et al.  Phosphorylation of Serine‐880 in GluR2 by Protein Kinase C Prevents Its C Terminus from Binding with Glutamate Receptor‐Interacting Protein , 1999, Journal of neurochemistry.

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

[61]  Philip R. Cohen,et al.  Structural basis for the recognition of regulatory subunits by the catalytic subunit of protein phosphatase 1 , 1997, The EMBO journal.

[62]  M. Bollen,et al.  The C-terminus of NIPP1 (nuclear inhibitor of protein phosphatase-1) contains a novel binding site for protein phosphatase-1 that is controlled by tyrosine phosphorylation and RNA binding. , 2000, The Biochemical journal.

[63]  R. Huganir,et al.  Interaction of the AMPA receptor subunit GluR2/3 with PDZ domains regulates hippocampal long-term depression , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[64]  G. Collingridge,et al.  PDZ Proteins Interacting with C-Terminal GluR2/3 Are Involved in a PKC-Dependent Regulation of AMPA Receptors at Hippocampal Synapses , 2000, Neuron.

[65]  J. Sanes,et al.  Can molecules explain long-term potentiation? , 1999, Nature Neuroscience.

[66]  Mark von Zastrow,et al.  Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD , 2000, Nature Neuroscience.

[67]  R. Colbran,et al.  Autophosphorylation-dependent Targeting of Calcium/ Calmodulin-dependent Protein Kinase II by the NR2B Subunit of theN-Methyl- d-aspartate Receptor* , 1998, The Journal of Biological Chemistry.