Cyclosporin A induces a biphasic increase in KCl-induced calcium influx in GH3 pituitary cells

The role of calcineurin in modulation of calcium channel activity was examined in GH3 pituitary cells by using its selective inhibitor cyclosporin A. While cyclosporin A had little effect on basal activity, it induced a biphasic increase in K+-induced Ca-45(2+) influx. Cyclosporin A rapidly increased K+-induced Ca-45(2+) influx to approximately 140% of control in 1 h and the increment maintained at this magnitude for 1-8 h. Thereafter, K+-induced Ca-45(2+) influx gradually increased further to approximately 220% after 24 h exposure to this compound. In the presence of anisomycin, however, the increase occurred at the latter phase was abolished, In addition, the increased calcium influx in cyclosporin A-pretreated cells had a similar sensitivity to KCl and verapamil as in untreated cells. Measurement of intracellular Ca2+ level by Fura-2 analysis indicated that [Ca2+]i increase induced by high K+ or vasoactive intestinal peptide was similarly augmented in cyclosporin A-pretreated cells. Thus the results of this study suggest that calcineurin may play a tonic control on L-type Ca2+ channel, and inhibition of this enzyme may induce a subsequently protein synthesis-dependent higher channel activity. (C) 1999 Academic Press.