title: Riluzole-induced block of voltage-gated Na+ current and activation of BKCa channels in cultured differentiated human skeletal muscle cells.
abstract: Riluzole is known to be of therapeutic use in the management of amyotrophic lateral sclerosis. In this study, we investigated the effects of riluzole on ion currents in cultured differentiated human skeletal muscle cells (dHSkMCs). Western blotting revealed the protein expression of alpha-subunits for both large-conductance Ca2+-activated K+ (BK(Ca)) channel and Na+ channel (Na(v)1.5) in these cells. Riluzole could reduce the frequency of spontaneous beating in dHSkMCs. In whole-cell configuration, riluzole suppressed voltage-gated Na+ current (I(Na)) in a concentration-dependent manner with an IC50 value of 2.3 microM. Riluzole (10 microM) also effectively increased Ca2+-activated K+ current (I(K(Ca))) which could be reversed by iberiotoxin (200 nM) and paxilline (1 microM), but not by apamin (200 nM). In inside-out patches, when applied to the inside of the cell membrane, riluzole (10 microM) increased BK(Ca)-channel activity with a decrease in mean closed time. Simulation studies also unraveled that both decreased conductance of I(Na) and increased conductance of I(K(Ca)) utilized to mimic riluzole actions in skeletal muscle cells could combine to decrease the amplitude of action potentials and increase the repolarization of action potentials. Taken together, inhibition of I(Na) and stimulation of BK(Ca)-channel activity caused by this drug are partly, if not entirely, responsible for its muscle relaxant actions in clinical setting.
authors: Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan.
authors: Ya-Jean
authors: YJ
authors: Wang
authors: Ming-Wei
authors: MW
authors: Lin
authors: An-An
authors: AA
authors: Lin
authors: Sheng-Nan
authors: SN
authors: Wu
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D002478:Cells, Cultured; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000096:biosynthesis / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010455:Peptides / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019782:Riluzole / Q000494:pharmacology*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D007211:Indoles; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010455:Peptides; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C048220:paxilline; C064719:iberiotoxin; D019782:Riluzole