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An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation

Nature volume 340, pages 554–557 (1989)Cite this article

Abstract

THE phenomenon of long-term potentiation (LTP), a long lasting increase in the strength of synaptic transmission which is due to brief, repetitive activation of excitatory afferent fibres, is one of the most striking examples of synaptic plasticity in the mammalian brain. In the CA1 region of the hippocampus, the induction of LTP requires activation of NMDA (N-methyl-D-aspartate) receptors by synaptically released glutamate1 with concomitant postsynaptic membrane depolarization2-5. This relieves the voltage-dependent magnesium block of the NMD A-receptor ion channel6,7, allowing calcium to flow into the dendritic spine8-10. Although calcium has been shown to be a necessary trigger for LTP (refs 11,12), little is known about the immediate biochemical processes that are activated by calcium and are responsible for LTP. The most attractive candidates have been calcium/cal-modulin-dependent protein kinase II (CaM-KII) (refs 13-16), protein kinase C (refs 17-19), and the calcium-dependent protease, calpain20. Extracellular application of protein kinase inhibitors to the hippocampal slice preparation blocks the induction of LTP (refs 21-23) but it is unclear whether this is due to a pre- and/or postsynaptic action. We have found that intracellular injection into CA1 pyramidal cells of the protein kinase inhibitor H-7, or of the calmodulin antagonist calmidazolium, blocks LTP. Further-more, LTP is blocked by the injection of synthetic peptides that are potent calmodulin antagonists and inhibit CaM-KII auto- and substrate phosphorylation. These findings demonstrate that in the postsynaptic cell both activation of calmodulin and kinase activity are required for the generation of LTP, and focus further attention on the potential role of CaM-KII in LTP.

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Author notes

  1. Roger A. Nicoll: To whom correspondence should be addressed.

Authors and Affiliations

  1. Departments of Psychiatry and Physiology, University of California, San Francisco, California, 94143, USA

    Robert C. Malenka

  2. Departments of Physiology and Pharmacology, University of California, San Francisco, California, 94143, USA

    Julie A. Kauer, David J. Perkel & Roger A. Nicoll

  3. Departments of Neurobiology and Anatomy, University of Texas Health Science Center, Houston, Texas, 77225, USA

    Michael D. Mauk & Paul T. Kelly

  4. Department of Neurology, University of Texas Health Science Center, Houston, Texas, 77225, USA

    M. Neal Waxham

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  5. Paul T. Kelly
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Malenka, R., Kauer, J., Perkel, D. et al. An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation. Nature 340, 554–557 (1989). https://doi.org/10.1038/340554a0

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