Cyclic ADP-ribose and Inositol 1,4,5-Trisphosphate as Alternate Second Messengers for Intracellular Ca2+ Mobilization in Normal and Diabetic β-Cells

• DOI: 10.1074/jbc.273.5.2497
• Publication Date: 2002-07-26T14:56:47Z
• Authors: Shin Takasawa; Takako Akiyama; Koji Nata; Michio Kuroki; Akira Tohgo; Naoya Noguchi; Seiichi Kobayashi; Ichiro Kato; Toshiaki Katada; Hiroshi Okamoto
• Keywords: Male; 0301 basic medicine; Adenosine Diphosphate Ribose; Cyclic ADP-Ribose; Membrane Glycoproteins; Mice, Obese; Inositol 1,4,5-Trisphosphate; GPI-Linked Proteins; ADP-ribosyl Cyclase 1; Antigens, Differentiation; Diabetes Mellitus, Experimental; Mice, Inbred C57BL; Islets of Langerhans; Mice; 03 medical and health sciences; Glucose; Antigens, CD; Insulin Secretion; Animals; Insulin; Calcium; ADP-ribosyl Cyclase

Intracellular Ca2+ mobilization occurs in a variety of cellular processes and is mediated by two major systems, the inositol 1,4, 5-trisphosphate (IP3) and cyclic ADP-ribose (cADPR) systems. cADPR has been proposed to be a second messenger for insulin secretion induced by glucose in pancreatic beta-cells (Takasawa, S., Nata, K., Yonekura, H., and Okamoto, H. (1993) Science 259, 370-373). Here we show that the cADPR signal system for insulin secretion is replaced by the IP3 system in diabetic beta-cells such as ob/ob mouse islets and RINm5F cells. We measured the cADPR content in these beta-cells by radioimmunoassay and found that the increase of the cADPR content by glucose did not occur in ob/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 hydrolase) and type 2 ryanodine receptor mRNAs were scarcely detected and, in contrast, an increased expression of IP3 receptor mRNAs was observed. The diabetic beta-cells secreted insulin rather by carbamylcholine than by glucose.