RyR2 and calpain-10 delineate a novel apoptosis pathway in pancreatic islets.
Cells are programmed to die when critical signaling and metabolic pathways are disrupted. Inhibiting the type 2 ryanodine receptor (RyR2) in human and mouse pancreatic beta-cells markedly increased apoptosis. This mode of programmed cell death was not associated with robust caspase-3 activation prompting a search for an alternative mechanism. Increased calpain activity and calpain gene expression suggested a role for a calpain-dependent death pathway. Using a combination of pharmacological and genetic approaches, we demonstrated that the calpain-10 isoform mediated ryanodine-induced apoptosis. Apoptosis induced by the fatty acid palmitate and by low glucose also required calpain-10. Ryanodine-induced calpain activation and apoptosis were reversed by glucagon-like peptide or short-term exposure to high glucose. Thus RyR2 activity seems to play an essential role in beta-cell survival in vitro by suppressing a death pathway mediated by calpain-10, a type 2 diabetes susceptibility gene with previously unknown function.
Johnson
James D
JD
Department of Internal Medicine, Washington University, St. Louis, Missouri 63110, USA.
Han
Zhiqiang
Z
Otani
Kenichi
K
Ye
Honggang
H
Zhang
Yan
Y
Wu
Hong
H
Horikawa
Yukio
Y
Misler
Stanley
S
Bell
Graeme I
GI
Polonsky
Kenneth S
KS
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D003620:Dantrolene / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D004763:Glucagon-Like Peptides; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D010169:Palmitic Acids / Q000737:chemistry; D010455:Peptides / Q000494:pharmacology; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D012433:Ryanodine / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology*; D013997:Time Factors
D010169:Palmitic Acids; D010455:Peptides; D020033:Protein Isoforms; D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D004763:Glucagon-Like Peptides; C015236:glucagon-like-immunoreactivity; C505407:CASP3 protein, human; D002154:Calpain; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; C415197:calpain 10; D003620:Dantrolene; D005947:Glucose; D002118:Calcium