CA2-INDUCED LOSS OF CA2+()CALMODULIN-DEPENDENT PROTEIN-KINASE-II ACTIVITY IN PANCREATIC BETA-CELLS/

Elevations in intracellular Ca2+ in electrically permeabilized islets of Langerhans produced rapid insulin secretory responses from beta-cel ls, but the Ca2+ induced secretion was not maintained and was irrespec tive of the pattern of administration of elevated Ca2+. Ca2+ insensiti ve beta-cells responded normally to activators of protein kinase C or cAMP-dependent kinase with increased insulin secretion. The loss of se cretory responsiveness to Ca2+ was paralleled by a reduction in Ca2+-i nduced protein phosphorylation. This was caused by a reduction in Ca2/calmodulin-dependent protein kinase II (CaMK II) activity in the dese nsitized cells, as assessed by measuring the phosphorylation of a CaMK II-specific exogenous substrate, autocamtide-2. The Ca2+-induced redu ctions in kinase activity and protein phosphorylation were not depende nt on the activation of Ca2+ dependent protein kinases and were not ca used by the activation of phosphoprotein phosphatases or of Ca2+-activ ated proteases. The concomitant reductions in caMK II activity and Ca2 +-induced insulin secretion suggest that the activation of CaMK II is required for normal insulin secretory responses to increased intracell ular Ca2+ concentrations.