Involvement of calcium/calmodulin-dependent protein kinases in the setting of a molecular switch involved in hippocampal LTP

Neuropharmacology. Apr-May 1998;37(4-5):535-44. doi: 10.1016/s0028-3908(98)00058-6.

Abstract

Long-term potentiation (LTP) is the form of synaptic plasticity most commonly associated with learning and memory. Studies using protein kinase inhibitors have suggested functional roles for several kinases in the induction of LTP in the CA1 region of the hippocampus, though the precise role of any given kinase has yet to be fully established. Here we report that the selective calcium/calmodulin-dependent protein kinase (CaMK) inhibitor KN-62 has two distinct actions on LTP. As reported previously, KN-62 (3 microM) prevented the induction of LTP. Here we show that KN-62 also prevents the setting of a molecular switch, initiated by the synaptic activation of (S)-alpha-methyl-4-carboxyphenylglycine (MCPG)-sensitive metabotropic glutamate (mGlu) receptors. There are two aspects of this work which might be considered surprising. First, the setting of the molecular switch was prevented by a concentration of KN-62 (1 microM) subthreshold for the inhibition of the induction of LTP per se. Second, the setting of the molecular switch, by the delivery of a tetanus (100 Hz, 1 s) in the presence of a specific NMDA receptor antagonist (R)-2-amino-5-phosphonopentanoate (AP5), reduced the sensitivity of LTP to KN-62, such that at a concentration of 3 microM it no longer blocked induction (though at 10 microM it did). This conditioning effect of a tetanus, delivered in the presence of AP5, was prevented by MCPG (200 microM). These data reveal unexpected complexities in the involvement of KN-62-sensitive processes (presumably CaMKII) in the induction of LTP. They suggest that activation of KN-62-sensitive processes leads to (at least) two phosphorylation steps with fundamentally different roles in synaptic plasticity within a single synapse. They also raise the possibility that CaMKII is an integral part of the MCPG-sensitive molecular switch mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • 2-Amino-5-phosphonovalerate / pharmacology
  • Animals
  • Benzoates / pharmacology
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinases / physiology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • Hippocampus / cytology
  • Hippocampus / enzymology*
  • Hippocampus / physiology*
  • In Vitro Techniques
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology*
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Perfusion
  • Rats
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Synapses / physiology

Substances

  • Benzoates
  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • alpha-methyl-4-carboxyphenylglycine
  • KN 62
  • 2-Amino-5-phosphonovalerate
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Glycine