Comparison of the effects of hydrogen peroxide, 4-hydroxy-2-nonenal and beta-amyloid (25-35) upon calcium signalling.
The neurotoxic beta-amyloid (Abeta) peptide fragment Abeta(25-35) has been suggested to exert its deleterious effects on cells via production of hydrogen peroxide. In human platelets and in the presence of DMSO to prevent production of hydroxyl radicals from hydrogen peroxide, both Abeta(25-35) and hydrogen peroxide were found to increase intracellular calcium levels. Hydrogen peroxide in addition reduced the calcium response to thrombin, whereas this was not seen with Abeta(25-35). A similar pattern of effects to those seen with hydrogen peroxide were also seen with the neurotoxic aldehyde lipid peroxidation product 4-hydroxy-2-nonenal (HNE). The initial increase in calcium produced by hydrogen peroxide was not affected by EGTA, but was partially prevented by dithiothreitol. The calcium response to Abeta(25-35) [which was also seen with Abeta(1-40) and Abeta(1-42) but not with the inactive peptide Abeta(40-1)] consisted of an EGTA-sensitive and an EGTA-resistant component, of which the latter was also sensitive to DTT. Hydrogen peroxide increased basal phosphoinositide breakdown in rat brain miniprisms and decreased the responses to noradrenaline, carbachol and veratrine. The specific binding of [3H]inositol-1,4,5-trisphosphate ([3H]Ins(1,4,5)P3) to its receptor recognition site in human platelet membranes was increased by Abeta(25-35) but remained unchanged following hydrogen peroxide treatment. It is concluded that under conditions where production of hydroxyl radicals from hydrogen peroxide is blocked, hydrogen peroxide and Abeta(25-35) produce their effects on calcium by affecting the mobilisation of intracellular calcium. The qualitative differences in the calcium responses of these two agents can be explained (a) by an additional effect of Abeta(25-35) upon calcium entry and (b) by differences in their effects upon the Ins(1,4,5)P3 receptor.
Department of Pharmacology, Umeå University, Sweden. cf@pharm.umu.se
C J
CJ
Fowler
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Y
Ando
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Tiger
D000447:Aldehydes / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000097:blood*; D015220:Calcium Channels / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D015544:Inositol 1,4,5-Trisphosphate / Q000097:blood; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007700:Kinetics; D010446:Peptide Fragments / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013917:Thrombin / Q000494:pharmacology
D000447:Aldehydes; D016229:Amyloid beta-Peptides; D015220:Calcium Channels; D002614:Chelating Agents; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D010446:Peptide Fragments; D010716:Phosphatidylinositols; D018160:Receptors, Cytoplasmic and Nuclear; C074636:amyloid beta-protein (25-35); D004533:Egtazic Acid; D015544:Inositol 1,4,5-Trisphosphate; D006861:Hydrogen Peroxide; D013917:Thrombin; C027576:4-hydroxy-2-nonenal; D002118:Calcium; D004229:Dithiothreitol