title: Dantrolene-induced inhibition of skeletal L-type Ca2+ current requires RyR1 expression.
abstract: Malignant hyperthermia (MH) is a pharmacogenetic disorder most often linked to mutations in the type 1 ryanodine receptor (RyR1) or the skeletal L-type Ca(2+) channel (Ca(V)1.1). The only effective treatment for an MH crisis is administration of the hydantoin derivative Dantrolene. In addition to reducing voltage induced Ca(2+) release from the sarcoplasmic reticulum, Dantrolene was recently found to inhibit L-type currents in developing myotubes by shifting the voltage-dependence of Ca(V)1.1 channel activation to more depolarizing potentials. Thus, the purpose of this study was to obtain information regarding the mechanism of Dantrolene-induced inhibition of Ca(V)1.1. A mechanism involving a general depression of plasma membrane excitability was excluded because the biophysical properties of skeletal muscle Na(+) current in normal mouse myotubes were largely unaffected by exposure to Dantrolene. However, a role for RyR1 was evident as Dantrolene failed to alter the amplitude, voltage dependence and inactivation kinetics of L-type currents recorded from dyspedic (RyR1 null) myotubes. Taken together, these results suggest that the mechanism of Dantrolene-induced inhibition of the skeletal muscle L-type Ca(2+) current is related to altered communication between Ca(V)1.1 and RyR1.
authors.affiliation: Division of Cardiology, Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, P-15 8006, B-139, Aurora, CO 80045, USA. roger.bannister@ucdenver.edu
authors.forename: R A
authors.initials: RA
authors.lastname: Bannister
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002478:Cells, Cultured; D003620:Dantrolene / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology; D018408:Patch-Clamp Techniques; D012433:Ryanodine / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
chemical_list: C529218:CACNA1S protein, mouse; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D003620:Dantrolene