Cations as Switches of Amyloid-Mediated Membrane Disruption Mechanisms: Calcium and IAPP

• Published in: Biophysical journal Vol. 104; no. 1; pp. 173 - 184
• Main Authors: Sciacca, Michele F.M., Milardi, Danilo, Messina, Grazia M.L., Marletta, Giovanni, Brender, Jeffrey R., Ramamoorthy, Ayyalusamy, La Rosa, Carmelo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.01.2013; Biophysical Society; The Biophysical Society
• Subjects: Amyloid; Amyloid - metabolism; Animals; Apoptosis; atomic force microscopy; Biophysics; calcium; Calcium - metabolism; Cations; Cell Membrane - metabolism; Coloring Agents; Cytotoxicity; death; Detergents - pharmacology; homeostasis; Humans; Hydrophobic and Hydrophilic Interactions - drug effects; Islet Amyloid Polypeptide - metabolism; Lipid Bilayers - chemistry; lipids; Membranes; metal ions; Microscopy, Atomic Force; noninsulin-dependent diabetes mellitus; nuclear magnetic resonance spectroscopy; Pathogenesis; Peptides; Phosphatidylcholines - chemistry; Phosphatidylglycerols - chemistry; Phosphatidylserines - chemistry; plasma membrane; polypeptides; Proteins; Proteins and Nucleic Acids; quartz; Quartz Crystal Microbalance Techniques; Rats
• ISSN: 0006-3495; 1542-0086
• DOI: 10.1016/j.bpj.2012.11.3811

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 Ca2+ 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 Ca2+ 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.