Cyclic ADP-ribose and inositol 1,4,5-trisphosphate as alternate second messengers for intracellular Ca2+ mobilization in normal and diabetic beta-cells.
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.
Takasawa
S
S
Department of Biochemistry, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-77, Miyagi, Japan.
Akiyama
T
T
Nata
K
K
Kuroki
M
M
Tohgo
A
A
Noguchi
N
N
Kobayashi
S
S
Kato
I
I
Katada
T
T
Okamoto
H
H
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis; D002118:Calcium / Q000378:metabolism*; D036563:Cyclic ADP-Ribose; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D058851:GPI-Linked Proteins; D005947:Glucose / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009244:NAD+ Nucleosidase / Q000096:biosynthesis; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D015290:Second Messenger Systems
D015703:Antigens, CD; D000943:Antigens, Differentiation; D058851:GPI-Linked Proteins; D007328:Insulin; D008562:Membrane Glycoproteins; D036563:Cyclic ADP-Ribose; D000246:Adenosine Diphosphate Ribose; D015544:Inositol 1,4,5-Trisphosphate; D036541:ADP-ribosyl Cyclase; C087521:ADP-ribosyl cyclase 2; C498155:Cd38 protein, mouse; C498156:Cd38 protein, rat; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1; D005947:Glucose; D002118:Calcium