A Mutant Sk Channel Rescued locomotion Defects in C. elegans ALS Model

Abstract

Small-conductance Ca2+-activated K+(SK) channels mediate medium afterhyperpolarization in the neurons which limits the firing frequency of action potentials and, thus, play a key role in the regulation of neuronal excitability. Given their importance in neurons, SK channels are potential drug targets for movement disorders, including ataxia and Amyotrophic Lateral Sclerosis (ALS). The SK channels are activated exclusively by the Ca2+-bound calmodulin. Here, we report that substitution of a valine to phenylalanine (V407F) in the SK2 channel caused a ∼6 fold increase in the Ca2+sensitivity. Subsequent tests with equivalent valine to phenylalanine substitutions in SK1 and SK3 channels also exhibited Ca2+hypersensitivity. Additionally, an equivalent phenylalanine substitution in the Caenorhabditis elegans (C. elegans) SK2 ortholog kcnl-2 partially rescued locomotion defects in an existing C. elegans ALS model, in which human SOD1G85R is expressed at high levels in neurons. This supports the idea that the phenylalanine substitution impacts SK channel function in vivo. This work for the first time provides a criticalreagent for future studies: an SK channel that is hypersensitive toCa2+concentrations with increased activity in vivo.