title: 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 Caenorhabditis elegans SMA models to identify modifiers of the SMN loss of function phenotypes. One class of such genetic modifiers was the small conductance, Ca(2+)-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. It is unclear if riluzole can extend life span 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 motor neuron 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 motor neuron function by acting on SK channels and suggest that SK channels may be important therapeutic targets for SMA patients.
authors.affiliation: Department of Neuroscience, Brown University, Providence, Rhode Island 02912, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Dimitriadi
authors.forename: Min Jeong
authors.initials: MJ
authors.lastname: Kye
authors.forename: Geetika
authors.initials: G
authors.lastname: Kalloo
authors.forename: Jill M
authors.initials: JM
authors.lastname: Yersak
authors.forename: Mustafa
authors.initials: M
authors.lastname: Sahin
authors.forename: Anne C
authors.initials: AC
authors.lastname: Hart
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000648:ultrastructure; D017173:Caenorhabditis elegans; D002478:Cells, Cultured; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques / Q000379:methods; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D009474:Neurons / Q000166:cytology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D019782:Riluzole / Q000494:pharmacology* / Q000627:therapeutic use; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000819:agonists*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics
chemical_list: D018696:Neuroprotective Agents; D051640:Small-Conductance Calcium-Activated Potassium Channels; D055533:Survival of Motor Neuron 1 Protein; D019782:Riluzole