Dantrolene-induced inhibition of skeletal L-type Ca 2 + 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 Ca2+ channel (CaV1.1). The only effective treatment for an MH crisis is administration of the hydantoin derivative Dantrolene. In addition to reducing voltage induced Ca2+ release from the sarcoplasmic reticulum, Dantrolene was recently found to inhibit L-type currents in developing myotubes by shifting the voltage-dependence of CaV1.1 channel activation to more depolarizing potentials. Thus, the purpose of this study was to obtain information regarding the mechanism of Dantrolene-induced inhibition of CaV1.1. 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 Ca2+ current is related to altered communication between CaV1.1 and RyR1. © 2013 R. A. Bannister.