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Casein kinase–II regulates NMDA channel function in hippocampal neurons

Nature Neuroscience volume 2, pages 125–132 (1999)Cite this article

Abstract

Several second–messenger–regulated protein kinases have been implicated in the regulation of N–methyl–D–aspartate (NMDA) channel function. Yet the role of calcium and cyclic–nucleotide–independent kinases, such as casein kinase II (CKII), has remained unexplored. Here we identify CKII as an endogenous Ser/Thr protein kinase that potently regulates NMDA channel function and mediates intracellular actions of spermine on the channel. The activity of NMDA channels in cell–attached and inside–out recordings was enhanced by CKII or spermine and was decreased by selective inhibition of CKII. In hippocampal slices, inhibitors of CKII reduced synaptic transmission mediated by NMDA but not AMPA receptors. The dependence of NMDA receptor channel activity on tonically active CKII thus permits changes in intracellular spermine levels or phosphatase activities to effectively control channel function.

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Figure 1: Effects of CaMKII and CKII inhibitors on NMDA channel function in cell–attached patches.
Figure 2: Extracellular spermine increases NMDA channel activity in cell–attached patches.
Figure 3: The effects of activation or inhibition of CKII on NMDA channel activity recorded in inside–out patches.
Figure 4: Inhibition of CKII selectively reduces the NMDA component of synaptic transmission in the dentate gyrus.

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Acknowledgements

We thank Jolinda Traugh for the gift of purified CKII, for the sharing of her biochemical findings, and for her comments on the manuscript. We thank Walter Pyerin for reviewing an earlier version of the manuscript, Georg Köhr for his early work with phorbol esters on NMDA channels and Brian Oyama for technical assistance. This work was supported by a Howard Hughes predoctoral fellowship to D.N.L and by the NINDS grant NS 27528 and the Coelho Endowment to I.M.

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  1. Neuroscience Graduate Program, Stanford University School of Medicine, Stanford, 94305, Californina, USA

    David N. Lieberman

  2. Departments of Neurology and Physiology, UCLA School of Medicine, Los Angeles, 90095–1769, California, USA

    Istvan Mody

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Correspondence to David N. Lieberman.

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Lieberman, D., Mody, I. Casein kinase–II regulates NMDA channel function in hippocampal neurons. Nat Neurosci 2, 125–132 (1999). https://doi.org/10.1038/5680

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