Mitogen-Activated Protein Kinase Upregulates the Dendritic Translation Machinery in Long-Term Potentiation by Controlling the Mammalian Target of Rapamycin Pathway

Protein synthesis is required for persistent forms of synaptic plasticity, including long-term potentiation (LTP). A key regulator of LTP-related protein synthesis is mammalian target of rapamycin (mTOR), which is thought to modulate translational capacity by facilitating the synthesis of particular components of the protein synthesis machinery. Recently, extracellularly regulated kinase (ERK) also was shown to mediate plasticity-related translation, an effect that may involve regulation of the mTOR pathway. We studied the interaction between the mTOR and ERK pathways in hippocampal LTP induced at CA3–CA1 synapses by high-frequency synaptic stimulation (HFS). Within minutes after HFS, the expression of multiple translational proteins, the synthesis of which is under the control of mTOR, increased in area CA1 stratum radiatum. This upregulation was detected in pyramidal cell dendrites and was blocked by inhibitors of the ERK pathway. In addition, ERK mediated the stimulation of mTOR by HFS. The possibility that ERK regulates mTOR by acting at a component further upstream in the phosphatidylinositide 3-kinase (PI3K)–mTOR pathway was tested by probing the phosphorylation of p90-S6 kinase, phosphoinositide-dependent kinase 1 (PDK1), and Akt. ERK inhibitors blocked HFS-induced phosphorylation of all three proteins at sites implicated in the regulation of mTOR. Moreover, a component of basal and HFS-induced ERK activity depended on PI3K, indicating that mTOR-mediated protein synthesis in LTP requires coincident and mutually dependent activity in the PI3K and ERK pathways. The role of ERK in regulating PDK1 and Akt, with their extensive effects on cellular function, has important implications for the coordinated response of the neuron to LTP-inducing stimulation.

[1]  P. Cohen,et al.  Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα , 1997, Current Biology.

[2]  Kenneth S Kosik,et al.  Neuronal RNA Granules A Link between RNA Localization and Stimulation-Dependent Translation , 2001, Neuron.

[3]  Maria Deak,et al.  Identification of a pocket in the PDK1 kinase domain that interacts with PIF and the C‐terminal residues of PKA , 2000, The EMBO journal.

[4]  T. Soderling,et al.  Bidirectional Regulation of Cytoplasmic Polyadenylation Element-binding Protein Phosphorylation by Ca 2ϩ / Calmodulin-dependent Protein Kinase Ii and Protein Phosphatase 1 during Hippocampal Long-term Potentiation Induction of Hippocampal Long-term Potentiation (ltp) Requires Activation of Ca 2ϩ /ca , 2022 .

[5]  Eric R Kandel,et al.  ERK Plays a Regulatory Role in Induction of LTP by Theta Frequency Stimulation and Its Modulation by β-Adrenergic Receptors , 1999, Neuron.

[6]  M. Constantine-Paton,et al.  NMDA receptor-mediated control of protein synthesis at developing synapses , 2000, Nature Neuroscience.

[7]  D. Amaral,et al.  A quantitative analysis of the dendritic organization of pyramidal cells in the rat hippocampus , 1995, The Journal of comparative neurology.

[8]  S. Gammeltoft,et al.  A phosphoserine‐regulated docking site in the protein kinase RSK2 that recruits and activates PDK1 , 2000, The EMBO journal.

[9]  A. Newton,et al.  Regulation of protein kinase C ζ by PI 3-kinase and PDK-1 , 1998, Current Biology.

[10]  A. Nairn,et al.  Glutamate-Dependent Phosphorylation of Elongation Factor-2 and Inhibition of Protein Synthesis in Neurons , 1997, The Journal of Neuroscience.

[11]  D. Johnston,et al.  Protein Kinase Modulation of Dendritic K+ Channels in Hippocampus Involves a Mitogen-Activated Protein Kinase Pathway , 2002, The Journal of Neuroscience.

[12]  D. Alessi,et al.  Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. , 1999, The Biochemical journal.

[13]  R. Pearson,et al.  Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70s6k , 1997, The EMBO journal.

[14]  E. Quinlan,et al.  CPEB-Mediated Cytoplasmic Polyadenylation and the Regulation of Experience-Dependent Translation of α-CaMKII mRNA at Synapses , 1998, Neuron.

[15]  H. Cline,et al.  Stabilization of dendritic arbor structure in vivo by CaMKII. , 1998, Science.

[16]  M. Kawamura,et al.  Brain-derived Neurotrophic Factor Enhances Neuronal Translation by Activating Multiple Initiation Processes , 2001, The Journal of Biological Chemistry.

[17]  M. Kennedy,et al.  Tetanic Stimulation Leads to Increased Accumulation of Ca2+/Calmodulin-Dependent Protein Kinase II via Dendritic Protein Synthesis in Hippocampal Neurons , 1999, The Journal of Neuroscience.

[18]  J. David Sweatt,et al.  A Requirement for the Mitogen-activated Protein Kinase Cascade in Hippocampal Long Term Potentiation* , 1997, The Journal of Biological Chemistry.

[19]  Hua Tang,et al.  Transduction of Growth or Mitogenic Signals into Translational Activation of TOP mRNAs Is Fully Reliant on the Phosphatidylinositol 3-Kinase-Mediated Pathway but Requires neither S6K1 nor rpS6 Phosphorylation , 2002, Molecular and Cellular Biology.

[20]  T. Freund,et al.  Total number and distribution of inhibitory and excitatory synapses on hippocampal CA1 pyramidal cells , 2001, Neuroscience.

[21]  S. Schreiber,et al.  Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Scott T. Wong,et al.  Cross Talk between ERK and PKA Is Required for Ca2+ Stimulation of CREB-Dependent Transcription and ERK Nuclear Translocation , 1998, Neuron.

[23]  K. Inoki,et al.  TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling , 2002, Nature Cell Biology.

[24]  M. Wick,et al.  Mechanism of Phosphorylation of Protein Kinase B/Akt by a Constitutively Active 3-Phosphoinositide-dependent Protein Kinase-1* , 2000, The Journal of Biological Chemistry.

[25]  E. Schuman,et al.  Dendritic Protein Synthesis, Synaptic Plasticity, and Memory , 2006, Cell.

[26]  Steven P Gygi,et al.  Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Hyejin Kang,et al.  Translational Control by MAPK Signaling in Long-Term Synaptic Plasticity and Memory , 2004, Cell.

[28]  P. Tsichlis,et al.  AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. , 1999, Annual review of biochemistry.

[29]  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.

[30]  S. Taylor,et al.  Phosphorylation and activation of cAMP-dependent protein kinase by phosphoinositide-dependent protein kinase. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[31]  A. Newton,et al.  Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1) , 1998, Current Biology.

[32]  J. Lehman,et al.  Mechanism of Ribosomal p70S6 Kinase Activation by Granulocyte Macrophage Colony-stimulating Factor in Neutrophils , 2003, Journal of Biological Chemistry.

[33]  A. Patapoutian,et al.  Trk receptors: mediators of neurotrophin action , 2001, Current Opinion in Neurobiology.

[34]  F. Bloom,et al.  Phosphatidylinositol 3-Kinase Is Required for the Expression But Not for the Induction or the Maintenance of Long-Term Potentiation in the Hippocampal CA1 Region , 2002, The Journal of Neuroscience.

[35]  J Cairns,et al.  Cold spring harbor. , 1991, Science.

[36]  J. Blenis,et al.  Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. , 2002, Molecular cell.

[37]  Eric R Kandel,et al.  Capture of the Late Phase of Long-Term Potentiation within and across the Apical and Basilar Dendritic Compartments of CA1 Pyramidal Neurons: Synaptic Tagging Is Compartment Restricted , 2006, The Journal of Neuroscience.

[38]  Ravi Iyengar,et al.  Postsynaptic signaling networks: Cellular cogwheels underlying long-term plasticity , 2005, Biological Psychiatry.

[39]  Wen G. Chen,et al.  BDNF Regulates the Translation of a Select Group of mRNAs by a Mammalian Target of Rapamycin-Phosphatidylinositol 3-Kinase-Dependent Pathway during Neuronal Development , 2004, The Journal of Neuroscience.

[40]  S. Davis,et al.  The MAPK/ERK Cascade Targets Both Elk-1 and cAMP Response Element-Binding Protein to Control Long-Term Potentiation-Dependent Gene Expression in the Dentate Gyrus In Vivo , 2000, The Journal of Neuroscience.

[41]  B. Hemmings,et al.  Ten years of protein kinase B signalling: a hard Akt to follow. , 2001, Trends in biochemical sciences.

[42]  U. Frey,et al.  Long-term potentiation induced in dendrites separated from rat's CA1 pyramidal somata does not establish a late phase , 1989, Neuroscience Letters.

[43]  N. Sonenberg,et al.  The Translation Repressor 4E-BP2 Is Critical for eIF4F Complex Formation, Synaptic Plasticity, and Memory in the Hippocampus , 2005, The Journal of Neuroscience.

[44]  A. Hanauer,et al.  Expression analysis of RSK gene family members: the RSK2 gene, mutated in Coffin-Lowry syndrome, is prominently expressed in brain structures essential for cognitive function and learning. , 2002, Human molecular genetics.

[45]  B. Vanhaesebroeck,et al.  The PI3K-PDK1 connection: more than just a road to PKB. , 2000, The Biochemical journal.

[46]  S. Grant,et al.  Phosphatidylinositol 3-Kinase Regulates the Induction of Long-Term Potentiation through Extracellular Signal-Related Kinase-Independent Mechanisms , 2003, The Journal of Neuroscience.

[47]  P. Cohen,et al.  Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1. , 1999, The Biochemical journal.

[48]  J. Silber,et al.  Functional Characterization of Human RSK4, a New 90-kDa Ribosomal S6 Kinase, Reveals Constitutive Activation in Most Cell Types* , 2005, Journal of Biological Chemistry.

[49]  G. Thomas,et al.  The modular phosphorylation and activation of p70s6k , 1997, FEBS letters.

[50]  J. David Sweatt,et al.  The MAPK cascade is required for mammalian associative learning , 1998, Nature Neuroscience.

[51]  A. Cuadrado,et al.  Activation of Akt/Protein Kinase B by G Protein-coupled Receptors , 1998, The Journal of Biological Chemistry.

[52]  T. Sacktor,et al.  Protein synthesis-dependent formation of protein kinase Mzeta in long- term potentiation , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[53]  Christine C. Hudson,et al.  A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. , 2000, Cancer research.

[54]  F. Liu,et al.  Mouse 3-Phosphoinositide-dependent Protein Kinase-1 Undergoes Dimerization and trans-Phosphorylation in the Activation Loop* , 2003, Journal of Biological Chemistry.

[55]  Colin B. Reese,et al.  3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase , 1997, Current Biology.

[56]  Kenta Hara,et al.  Brain-Derived Neurotrophic Factor Induces Mammalian Target of Rapamycin-Dependent Local Activation of Translation Machinery and Protein Synthesis in Neuronal Dendrites , 2004, The Journal of Neuroscience.

[57]  Paul Tempst,et al.  Phosphorylation and Functional Inactivation of TSC2 by Erk Implications for Tuberous Sclerosisand Cancer Pathogenesis , 2005, Cell.

[58]  U. Frey,et al.  Weak before strong: dissociating synaptic tagging and plasticity-factor accounts of late-LTP , 1998, Neuropharmacology.

[59]  Ravi Iyengar,et al.  Local Protein Synthesis Mediates a Rapid Increase in Dendritic Elongation Factor 1A after Induction of Late Long-Term Potentiation , 2005, The Journal of Neuroscience.

[60]  Eric R. Kandel,et al.  Expression of Constitutively Active CREB Protein Facilitates the Late Phase of Long-Term Potentiation by Enhancing Synaptic Capture , 2002, Cell.

[61]  S. Gygi,et al.  Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. , 1999, Genes & development.

[62]  U. Frey,et al.  Anisomycin, an inhibitor of protein synthesis, blocks late phases of LTP phenomena in the hippocampal CA1 region in vitro , 1988, Brain Research.

[63]  S. Tonegawa,et al.  A clustered plasticity model of long-term memory engrams , 2006, Nature Reviews Neuroscience.

[64]  J. Hofsteenge,et al.  Identification of Tyrosine Phosphorylation Sites on 3-Phosphoinositide-dependent Protein Kinase-1 and Their Role in Regulating Kinase Activity* , 2001, The Journal of Biological Chemistry.

[65]  A. Gingras,et al.  A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[66]  M. Bear,et al.  A Role for the Cytoplasmic Polyadenylation Element in NMDA Receptor-Regulated mRNA Translation in Neurons , 2001, The Journal of Neuroscience.

[67]  P. Gean,et al.  A Role for the PI-3 Kinase Signaling Pathway in Fear Conditioning and Synaptic Plasticity in the Amygdala , 2001, Neuron.

[68]  E. Schuman,et al.  A Requirement for Local Protein Synthesis in Neurotrophin-Induced Hippocampal Synaptic Plasticity , 1996, Science.

[69]  J. Blenis,et al.  Identification of S6 Kinase 1 as a Novel Mammalian Target of Rapamycin (mTOR)-phosphorylating Kinase* , 2005, Journal of Biological Chemistry.

[70]  C. Vickers,et al.  Induction and maintenance of late‐phase long‐term potentiation in isolated dendrites of rat hippocampal CA1 pyramidal neurones , 2005, The Journal of physiology.

[71]  A. Bode,et al.  Signal Transduction Pathways Involved in Phosphorylation and Activation of p70S6K Following Exposure to UVA Irradiation* , 2001, The Journal of Biological Chemistry.

[72]  P. Serrano,et al.  Protein synthesis‐dependent LTP in isolated dendrites of CA1 pyramidal cells , 2005, Hippocampus.

[73]  D. V. van Aalten,et al.  PDK1, the master regulator of AGC kinase signal transduction. , 2004, Seminars in cell & developmental biology.

[74]  J. Richter,et al.  Molecular mechanisms for activity-regulated protein synthesis in the synapto-dendritic compartment , 2000, Current Opinion in Neurobiology.

[75]  E. Klann,et al.  NMDA receptor activation results in PKA‐ and ERK‐dependent Mnk1 activation and increased eIF4E phosphorylation in hippocampal area CA1 , 2004, Journal of neurochemistry.

[76]  U. Frey,et al.  Synaptic tagging and long-term potentiation , 1997, Nature.

[77]  Tian Xu,et al.  Akt regulates growth by directly phosphorylating Tsc2 , 2002, Nature Cell Biology.

[78]  Eric Klann,et al.  Activation of the Phosphoinositide 3-kinase–akt–mammalian Target of Rapamycin Signaling Pathway Is Required for Metabotropic Glutamate Receptor-dependent Long-term Depression , 2022 .

[79]  P. Sanna,et al.  Time-restricted role for dendritic activation of the mTOR-p70S6K pathway in the induction of late-phase long-term potentiation in the CA1 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[80]  C. Proud,et al.  Eukaryotic initiation factor 2B: identification of multiple phosphorylation sites in the ϵ‐subunit and their functions in vivo , 2001, The EMBO journal.

[81]  Yi-shuian Huang,et al.  N‐methyl‐D‐aspartate receptor signaling results in Aurora kinase‐catalyzed CPEB phosphorylation and αCaMKII mRNA polyadenylation at synapses , 2002, The EMBO journal.

[82]  Takashi Tsuruo,et al.  Regulation of Kinase Activity of 3-Phosphoinositide-dependent Protein Kinase-1 by Binding to 14-3-3* , 2002, The Journal of Biological Chemistry.