A role for calcineurin (protein phosphatase-2B) in the regulation of glutamate release.
Previous studies have shown that 4-aminopyridine (4AP) induced Ca-influx 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 synaptosomes with the immunosuppressant, FK506, an inhibitor of protein phosphatase-2B (calcineurin). FK506 did not inhibit the Ca-independent release of glutamate from a cytosolic pool. Examination of the effect of FK506 on the influx of Ca elicited by 4AP indicated that inhibition of calcineurin activity resulted in an increase of voltage-dependent Ca-influx. Based on these results, we suggest that protein dephosphorylation effected by calcineurin may suppress voltage-dependent Ca-channel activity and in so doing inhibits evoked glutamate release. Activation of calcineurin produced by initial Ca-entry may represent a negative feedback to limit the activity of Ca-channels coupled to the release of glutamate.
Sihra
T S
TS
Department of Pharmacology, Royal Free Hospital School of Medicine, University of London, U.K.
Nairn
A C
AC
Kloppenburg
P
P
Lin
Z
Z
Pouzat
C
C
D000632:Aminopyrine / Q000494:pharmacology; D000818:Animals; D019703:Calcineurin; D002118:Calcium / Q000494:pharmacology; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D002540:Cerebral Cortex / Q000378:metabolism*; D004357:Drug Synergism; D004533:Egtazic Acid / Q000494:pharmacology; D005089:Exocytosis; D018698:Glutamic Acid / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats; D013574:Synaptosomes / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology
D002148:Calmodulin-Binding Proteins; D000632:Aminopyrine; D018698:Glutamic Acid; D004533:Egtazic Acid; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D002118:Calcium; D016559:Tacrolimus