Journal
APOPTOSIS
Volume 14, Issue 7, Pages 878-889Publisher
SPRINGER
DOI: 10.1007/s10495-009-0364-4
Keywords
Ceramide; Kv channels; Cell death; Insulin; Amylin
Categories
Funding
- Deutsche Forschungsgemeinschaft [La 315/6-1, La 315/13-1, GRK1302/1]
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Amyloid peptides interfere with survival of pancreatic beta-cells. In some cells apoptosis is paralleled by ceramide-dependent alterations of ion channel activity. The purpose of the present study was to elucidate the dependence of amyloid peptides A beta(1-42) and islet amyloid polypeptide (IAPP)-induced cell death on ceramide formation and ion channel activity in murine pancreatic islet cells. As disclosed by TUNEL (terminal dUTP nick-end labelling) and cleaved caspase 3 staining, apoptotic cell death was induced by A beta(1-42), IAPP and exogenously added C2-ceramide in islet cells from wild type mice. In islet cells from acid sphingomyelinase-deficient mice (ASM-KO) A beta(1-42) and IAPP but not exogenously added N-acetyl-D-sphingosine (C2-ceramide, 20 mu M) failed to stimulate apoptosis. Immunofluorescent staining revealed a stimulatory effect of A beta(1-42) on ceramide formation. According to patch clamp experiments, administration of A beta(1-42) and IAPP significantly decreased outwardly rectifying whole cell currents in wild type but not in ASMKO islet cells. C2-ceramide but not inactive di-ceramide (20 mu M) mimicked the inhibitory effect on Kv channel current. In conclusion, amyloid peptides induce apoptosis of pancreatic islet cells at least in part through activation of acid sphingomyelinase resulting in production of ceramide and subsequent inhibition of ion channel activity.
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