Sphingomyelinase dependent apoptosis following treatment of pancreatic beta-cells with amyloid peptides Abeta(1-42) or IAPP.
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 Abeta(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 Abeta(1-42), IAPP and exogenously added C2-ceramide in islet cells from wild type mice. In islet cells from acid sphingomyelinase-deficient mice (ASMKO) Abeta(1-42) and IAPP but not exogenously added N-acetyl-D-sphingosine (C2-ceramide, 20 microM) failed to stimulate apoptosis. Immunofluorescent staining revealed a stimulatory effect of Abeta(1-42) on ceramide formation. According to patch clamp experiments, administration of Abeta(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 microM) 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.
Zhang
Ying
Y
Department of Physiology, University of Tübingen, Tübingen, Germany.
Ranta
Felicia
F
Tang
Cai
C
Shumilina
Ekaterina
E
Mahmud
Hasan
H
Föller
Michael
M
Ullrich
Susanne
S
Häring
Hans-Ulrich
HU
Lang
Florian
F
D000682:Amyloid / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002518:Ceramides / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D058228:Islet Amyloid Polypeptide; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology*; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism*
D000682:Amyloid; D016229:Amyloid beta-Peptides; D002518:Ceramides; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D013108:Sphingomyelin Phosphodiesterase