CYCLIC ADP-RIBOSE AND INOSITOL 1,4,5-TRISPHOSPHATE AS ALTERNATE 2ND MESSENGERS FOR INTRACELLULAR CA2-CELLS( MOBILIZATION IN NORMAL AND DIABETIC BETA)

Intracellular Ca2+ mobilization occurs in a variety of cellular proces ses and is mediated by two major systems, the inositol 1,4,5-trisphosp hate (IP3) and cyclic ADP-ribose (cADPR) systems, cADPR has been propo sed to be a second messenger for insulin secretion induced by glucose in pancreatic beta-cells (Takasawa, S., Nata, K., Yonekura, H., and Ok amoto, H. (1993) Science 259, 370-373). Here we show that the cADPR si gnal system for insulin secretion is replaced by the IP3 system in dia betic beta-cells such as ob/ob mouse islets and RINm5F cells. We measu red the cADPR content in these beta-cells by radioimmunoassay and foun d that the increase of the cADPR content by glucose did not occur in o b/ob mouse islets and RINm5F cells, whereas the increased cADPR level by glucose was observed in normal rat and mouse islets, Microsomes of these diabetic beta-cells released Ca2+ in response to IP3 but not to cADPR. In the diabetic beta-cells, CD38 (ADP-ribosyl cyclase/cADPR hyd rolase) and type 2 ryanodine receptor mRNAs were scarcely detected and , in contrast, an increased expression of IP3 receptor mRNAs was obser ved, The diabetic beta-cells secreted insulin rather by carbamylcholin e than by glucose.