title: Cations as switches of amyloid-mediated membrane disruption mechanisms: calcium and IAPP.
abstract: Disruption of the integrity of the plasma membrane by amyloidogenic proteins is linked to the pathogenesis of a number of common age-related diseases. Although accumulating evidence suggests that adverse environmental stressors such as unbalanced levels of metal ions may trigger amyloid-mediated membrane damage, many features of the molecular mechanisms underlying these events are unknown. Using human islet amyloid polypeptide (hIAPP, aka amylin), an amyloidogenic peptide associated with β-cell death in type 2 diabetes, we demonstrate that the presence of Ca(2+) ions inhibits membrane damage occurring immediately after the interaction of freshly dissolved hIAPP with the membrane, but significantly enhances fiber-dependent membrane disruption. In particular, dye leakage, quartz crystal microbalance, atomic force microscopy, and NMR experiments show that Ca(2+) ions promote a shallow membrane insertion of hIAPP, which leads to the removal of lipids from the bilayer through a detergent-like mechanism triggered by fiber growth. Because both types of membrane-damage mechanisms are common to amyloid toxicity by most amyloidogenic proteins, it is likely that unregulated ion homeostasis, amyloid aggregation, and membrane disruption are all parts of a self-perpetuating cycle that fuels amyloid cytotoxicity.
authors: Biophysics, University of Michigan, Ann Arbor, Michigan, USA.
authors: Michele F M
authors: MF
authors: Sciacca
authors: Danilo
authors: D
authors: Milardi
authors: Grazia M L
authors: GM
authors: Messina
authors: Giovanni
authors: G
authors: Marletta
authors: Jeffrey R
authors: JR
authors: Brender
authors: Ayyalusamy
authors: A
authors: Ramamoorthy
authors: Carmelo
authors: C
authors: La Rosa
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002412:Cations; D002462:Cell Membrane / Q000378:metabolism*; D004396:Coloring Agents; D003902:Detergents / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions / Q000187:drug effects; D058228:Islet Amyloid Polypeptide / Q000378:metabolism*; D008051:Lipid Bilayers / Q000737:chemistry; D018625:Microscopy, Atomic Force; D010713:Phosphatidylcholines / Q000737:chemistry; D010715:Phosphatidylglycerols / Q000737:chemistry; D010718:Phosphatidylserines / Q000737:chemistry; D058525:Quartz Crystal Microbalance Techniques; D051381:Rats
chemical_list: D000682:Amyloid; D002412:Cations; D004396:Coloring Agents; D003902:Detergents; D058228:Islet Amyloid Polypeptide; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; D010718:Phosphatidylserines; C552372:lysomyristoylphosphatidylglycerol; C050294:1-palmitoyl-2-oleoylglycero-3-phosphoserine; D002118:Calcium; C028694:1-palmitoyl-2-oleoylphosphatidylcholine