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Regulation of NMDA channel function by endogenous Ca2+-dependent phosphatase

Nature volume 369, pages 235–239 (1994)Cite this article

Abstract

PROTEIN kinases modulate the activity of several ligand-gated ion channels1, including the NMDA (N-methyl-D-aspartate)2 subtype of glutamate receptor. Although phosphorylation and dephosphorylation of glutamate receptors may participate in several lasting physiological and pathological alterations of neuronal excitability3–7, the physiological control of this cycle for NMDA channels has not yet been established. Using cell-attached recordings in acutely dissociated adult rat dentate gyrus granule cells, we now demonstrate that inhibitors of an endogenous serine/threonine phosphatase prolong the duration of single NMDA channel openings, bursts, clusters and superclusters. Okadaic acid, a non-selective phosphatase inhibitor, prolongs channel openings only at a concentration that inhibits the Ca2+/calmodulin-dependent phosphatase 2B (calcineurin)8, and is ineffective when Ca2+ entry through NMDA channels is prevented. Furthermore, FK506, an inhibitor of calcineurin9,10, mimics the effects of okadaic acid. Thus in adult neurons, calcineurin, activated by calcium entry through native NMDA channels, shortens the duration of channel openings. Simulated synaptic currents11 were enhanced after phosphatase inhibition, which is consistent with the importance of phosphorylation of the NMDA-receptor complex in the short- and long-term control of neuronal excitability.

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Author notes

  1. Istvan Mody: To whom correspondence should be addressed.

Affiliations

  1. Neurosciences Graduate Program, Stanford University School of Medicine, Stanford, California, 94305, USA

    David N. Lieberman

  2. Department of Anesthesiology and Pain Management, University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas, 75235-9068, USA

    Istvan Mody

Authors
  1. David N. Lieberman
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  2. Istvan Mody
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Lieberman, D., Mody, I. Regulation of NMDA channel function by endogenous Ca2+-dependent phosphatase. Nature 369, 235–239 (1994). https://doi.org/10.1038/369235a0

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