alpha-Synuclein forms non-selective cation channels and stimulates ATP-sensitive potassium channels in hippocampal neurons

摘要

In Parkinson's disease and several other neurodegenerative diseases, the protein -synuclein (S) is produced within neurons and accumulates in the extracellular fluid. Several mechanisms of S action are proposed, one of which is the formation of cation-permeable pores that may mediate toxicity. S induces non-selective cation channels in lipid bilayers, but whether this occurs in living neurons and which properties the channels possess have not yet been examined. In this study the properties of S channels in dissociated hippocampal neurons are documented. In cell-attached recordings the incorporation of S into membranes was driven by applied negative potentials. These channels exhibited multiple levels of conductance (30, 70 and 120pS at -100mV) and inward rectification. The persistent activity of S channels induced local changes in intracellular Na+ and Ca2+, depolarized neurons and augmented bursting activity. S channels formed by adding S to the intracellular membrane in inside-out patches exhibited outward rectification. S channels were equally permeable to Na+, K+ and Ca2+. These channels were also observed in neurons transfected with wild-type or mutant A53T S, and after extracellular application of wild-type or mutant A53T S proteins. Opening of S channels stimulated opening of ATP-sensitive K+ (K-ATP ) channels and did not interfere with the activity of delayed rectifier K+ channels. The properties of S channels in neuronal membranes suggest stronger toxicity of extracellularly applied S than intracellular S. Enhancement of neuronal excitability and distortions in ion homeostasis may underlie the toxic effects of S that can be dampened by K-ATP channels.