Differential modulation of cortical synaptic activity by calcineurin (phosphatase 2B) versus phosphatases 1 and 2A

Gail D. Thomas, Brian O'Rourke, Robert Sikkink, Frank Rusnak, Eduardo Marban, Ronald G. Victor

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Reversible protein phosphorylation is thought to play an important regulatory role in synaptic neurotransmission. We recently have shown in cultured rat cortical neurons that inhibition of the Ca2+/calmodulin-dependent phosphatase calcineurin (phosphatase 2B) increases the frequency, but not the amplitude, of postsynaptic glutamatergic currents, implicating a presynaptic site of action for calcineurin. The specific presynaptic phosphoprotein substrates for calcineurin are unknown, however, calcineurin has been implicated in the control of the Ca2+-independent phosphatases, phosphatases 1 and 2A. To determine whether calcineurin's effects on synaptic transmission are direct or are mediated by changes in phosphatase 1 and/or 2A activities, we used whole-cell voltage clamp to record spontaneous and miniature excitatory postsynaptic currents in the presence of calyculin A (1 μM in bath solution), a membrane permeant inhibitor of phosphatases 1 and 2A which has no effect on calcineurin. Calyculin increased postsynaptic current amplitude without changing current frequency. In these same neurons, subsequent inhibition of calcineurin with cyclosporine A or FK506 had no further effect on current amplitude, but increased current frequency. The increased current amplitude seen with calyculin involved a postsynaptic mechanism, since the effect was reproduced by microcystin (10 μM in pipette solution), which is a membrane-impermeant inhibitor of phosphatases 1 and 2A. Thus, in rat cortical neurons, glutamatergic neurotransmission appears to be frequency-modulated through a presynaptic mechanism by calcineurin, and amplitude-modulated through a postsynaptic mechanism by phosphatases 1 and 2A.

Original languageEnglish (US)
Pages (from-to)101-108
Number of pages8
JournalBrain research
Volume749
Issue number1
DOIs
StatePublished - Feb 21 1997

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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