Increased Phosphorylation of Ca/Calmodulin-dependent Protein Kinase II and Its Endogenous Substrates in the Induction of Long Term Potentiation (*)

Induction of long term potentiation in the CA1 region of hippocampal slices is associated with increased activity of Ca/calmodulin-dependent protein kinase II (CaM kinase II) (Fukunaga, K., Stoppini, L., Miyamoto, E., and Muller, D.(1993) J. Biol. Chem. 268, 7863-7867). Here we report that application of high but not low frequency stimulation to two groups of afferents in the CA1 region of P-labeled slices resulted in the phosphorylation of two major substrates of this enzyme, synapsin I and microtubule-associated protein 2, as well as in the autophosphorylation of CaM kinase II. Furthermore, immunoblotting analysis revealed that long term potentiation induction was associated with an increase in the amount of CaM kinase II in the same region. All these changes were prevented when high frequency stimulation was applied in the presence of the N-methyl-D-aspartate receptor antagonist, D-2-amino-5-phosphonopentanoate. These results indicate that activation of CaM kinase II is involved in the induction of synaptic potentiation in both the postsynaptic and presynaptic regions.

[1]  K. Fukunaga,et al.  Immunohistochemical Localization of Ca2+/Calmodulin‐Dependent Protein Kinase II in Rat Brain and Various Tissues , 1988, Journal of neurochemistry.

[2]  D. L. Benson,et al.  Dendritic localization of type II calcium calmodulin-dependent protein kinase mRNA in normal and reinnervated rat hippocampus , 1992, Neuroscience.

[3]  Stephen G. Miller,et al.  Sequences of autophosphorylation sites in neuronal type II CaM kinase that control Ca2+-independent activity , 1988, Neuron.

[4]  T. Bliss,et al.  Arachidonic acid induces a long-term activity-dependent enhancement of synaptic transmission in the hippocampus , 1989, Nature.

[5]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[6]  Antonio Malgaroli,et al.  Glutamate-induced long-term potentiation of the frequency of miniature synaptic currents in cultured hippocampal neurons , 1992, Nature.

[7]  D. Muller,et al.  Enhancement of AMPA‐mediated Synaptic Transmission by the Protein Phosphatase Inhibitor Calyculin A in Rat Hippocampal Slices , 1993, The European journal of neuroscience.

[8]  T. Soderling,et al.  Ca2+/calmodulin-dependent protein kinase II. Identification of a regulatory autophosphorylation site adjacent to the inhibitory and calmodulin-binding domains. , 1988, The Journal of biological chemistry.

[9]  R. Tsien,et al.  Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP. , 1989, Science.

[10]  Aryeh Routtenberg,et al.  Protein kinase C inhibitors eliminate hippocampal long-term potentiation , 1987, Brain Research.

[11]  G. V. Goddard,et al.  Maintenance of long-term potentiation in rat dentate gyrus requires protein synthesis but not messenger RNA synthesis immediately post-tetanization , 1989, Neuroscience.

[12]  P. Greengard,et al.  Amino acid sequences surrounding the cAMP-dependent and calcium/calmodulin-dependent phosphorylation sites in rat and bovine synapsin I. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[13]  T. Soderling,et al.  Phosphorylation and regulation of glutamate receptors by calcium/calmodulin-dependent protein kinase II , 1993, Nature.

[14]  T. Soderling,et al.  Activation of Ca2+/calmodulin-dependent protein kinase II in cerebellar granule cells by N-methyl-d-aspartate receptor activation , 1990, Molecular and Cellular Neuroscience.

[15]  M. Waxham,et al.  In situ hybridization histochemistry of Ca2+/calmodulin-dependent protein kinase in developing rat brain , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[16]  S. J. Chen,et al.  Persistent protein kinase activation in the maintenance phase of long-term potentiation. , 1991, The Journal of biological chemistry.

[17]  S. J. Chen,et al.  Increased Phosphorylation of a 17‐kDa Protein Kinase C Substrate (P17) in Long‐Term Potentiation , 1992, Journal of neurochemistry.

[18]  M. Kennedy,et al.  Regional distribution of type II Ca2+/calmodulin-dependent protein kinase in rat brain , 1985, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[19]  T. Soderling,et al.  Activation of Ca2+/calmodulin-dependent protein kinase II and protein kinase C by glutamate in cultured rat hippocampal neurons. , 1992, The Journal of biological chemistry.

[20]  D. Terrian,et al.  mRNA at the synapse: analysis of a synaptosomal preparation enriched in hippocampal dendritic spines , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[21]  D. Madison,et al.  A requirement for the intercellular messenger nitric oxide in long-term potentiation. , 1991, Science.

[22]  R. Corradetti,et al.  Phosphorylation of the presynaptic protein B-50 (GAP-43) is increased during electrically induced long-term potentiation , 1992, Neuron.

[23]  Y. Ben-Ari,et al.  Rapid activation of hippocampal casein kinase II during long-term potentiation. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[24]  E. Kandel,et al.  Tests of the roles of two diffusible substances in long-term potentiation: evidence for nitric oxide as a possible early retrograde messenger. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[25]  P. Greengard,et al.  Ca2+/calmodulin-dependent protein kinase II: identification of threonine-286 as the autophosphorylation site in the alpha subunit associated with the generation of Ca2+-independent activity. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Alcino J. Silva,et al.  Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. , 1992, Science.

[27]  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.

[28]  Hiroshi Kase,et al.  Inhibitors of calmodulin and protein kinase C block different phases of hippocampal long-term potentiation , 1988, Brain Research.

[29]  T. Sacktor,et al.  Persistent activation of the zeta isoform of protein kinase C in the maintenance of long-term potentiation. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[30]  D. Muller,et al.  Long-term potentiation is associated with an increased activity of Ca2+/calmodulin-dependent protein kinase II. , 1993, The Journal of biological chemistry.

[31]  P. Greengard,et al.  Immunocytochemical localization of calcium/calmodulin-dependent protein kinase II in rat brain. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[32]  P. Greengard,et al.  Multiple phosphorylation sites in protein I and their differential regulation by cyclic AMP and calcium. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[33]  P. Greengard,et al.  Effects of synapsin I and calcium/calmodulin-dependent protein kinase II on spontaneous neurotransmitter release in the squid giant synapse. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[34]  K. Fukunaga,et al.  Activation of Ca2+/calmodulin-dependent protein kinase II and phosphorylation of intermediate filament proteins by stimulation of glutamate receptors in cultured rat cortical astrocytes. , 1994, The Journal of biological chemistry.

[35]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.

[36]  F. Morrell,et al.  Structural synaptic plasticity associated with the induction of long‐term potentiation is preserved in the dentate gyrus of aged rats , 1992, Hippocampus.

[37]  O. Steward,et al.  Differential subcellular localization of particular mRNAs in hippocampal neurons in culture , 1990, Neuron.

[38]  Chikako,et al.  Monoclonal antibodies against rat brain protein kinase C and their application to immunocytochemistry in nervous tissues , 1987, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[39]  J. Eberwine,et al.  Stimulus-induced coordinate changes in mRNA abundance in single postsynaptic hippocampal CA1 neurons , 1992, Neuron.

[40]  R. Nicoll,et al.  An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation , 1989, Nature.