The Neuroprotective Drug Riluzole Acts via Small Conductance Ca²⁺-Activated K⁺Channels to Ameliorate Defects in Spinal Muscular Atrophy Models

Abstract

Spinal muscular atrophy (SMA), a recessive neuromuscular disorder, is caused by diminished function of the Survival Motor Neuron (SMN) protein. To define the cellular processes pertinent to SMA, parallel genetic screens were undertaken in Drosophila and C. elegans SMA models to identify modifiers of the SMN loss of function phenotypes. One class of such genetic modifiers was the small conductance, Ca2+-activated K+ (SK) channels. SK channels allow efflux of potassium ions when intracellular calcium increases and can be activated by the neuroprotective drug riluzole. The latter is the only drug with proven, albeit modest, efficacy in the treatment of Amyotrophic Lateral Sclerosis (ALS). It is unclear if riluzole can extend lifespan or ameliorate symptoms in SMA patients as previous studies were limited and of insufficient power to draw any conclusions. The critical biochemical target of riluzole in motorneuron disease is not known, but the pharmacological targets of riluzole include SK channels. We examine here the impact of riluzole in two different SMA models. In vertebrate neurons, riluzole treatment restored axon outgrowth caused by diminished SMN. Additionally, riluzole ameliorated the neuromuscular defects in a C. elegans SMA model and SK channel function was required for this beneficial effect. We propose that riluzole improves motorneuron function by acting on SK channels and suggest that SK channels may be important therapeutic targets for SMA patients.

The survival motor neuron genesmn-1interacts with the U2AF large subunit geneuaf-1to regulateCaenorhabditis eleganslifespan and motor functions

“…We also suggest that mutations of the U2AF large subunit gene uaf-1 might be protective modifiers of smn-1 loss-of-function mutants. Together with previous studies of other SMN modifiers, 18,[26][27][28][29][30]45 our findings should facilitate the understanding of SMN functions.…”

The Glutamate Hypothesis in ALS: Pathophysiology and Drug Development

“…-dependent K + current [127,128], and inhibition of voltage-gated Ca 2+ channels [120,129,130]. Riluzole may also have independent effects, influencing both central and peripheral nerve function as shown by partial normalization of cortical hyperexcitability and a reduction of transient Na + conductances [131].…”

Neuroprotective Effect of the Novel Compound ITH33/IQM9.21 Against Oxidative Stress and Na+ and Ca2+ Overload in Motor Neuron-like NSC-34 Cells

“…-dependent K ? channels (Maroto et al 2011) and riluzole is activating them (Dimitriadi et al 2013), some of the differences about their mechanism of actions might be explained by their different effect on K ? currents.…”

“…-dependent outward K ? current activation (Dimitriadi et al 2013;Wang et al 2008), and modulates different types of K ? currents (Bellingham 2011), and other actions in various intracellular proteins involved in second messenger Neurotox Res systems (Noh et al 2000).…”