A ROLE FOR CALCINEURIN (PROTEIN PHOSPHATASE-2B) IN THE REGULATION OF GLUTAMATE RELEASE

Previous studies have shown that 4-aminopyridine (4AP) induced Ca-infl ux effects the release of glutamate from nerve terminals (synaptosomes ) isolated from rat cerebral cortex. We now show that the Ca-dependent component of this release is potentiated by preincubation of the syna ptosomes with the immunosuppressant, FK506, an inhibitor of protein ph osphatase-2B (calcineurin). FK506 did not inhibit the Ca-independent r elease of glutamate from a cytosolic pool. Examination of the effect o f FK506 on the influx of Ca elicited by 4AP indicated that inhibition of calcineurin activity resulted in an increase of voltage-dependent C a-influx. Based on these results, we suggest that protein dephosphoryl ation effected by calcineurin may suppress voltage-dependent Ca-channe l activity and in so doing inhibits evoked glutamate release. Activati on of calcineurin produced by initial Ca-entry may represent a negativ e feedback to limit the activity of Ca-channels coupled to the release of glutamate. (C) 1995 Academic Press, Inc.