Dantrolene Shifts the Affinity of the Ryanodine Receptor for MG2+

Abstract

Dantrolene is the only approved drug for the treatment of life-threatening malignant hyperthermia episodes. It has been shown by several studies that the voltage-dependent Ca2+ transient or force response is reduced by dantrolene; and indeed a binding domain for dantrolene on the ryanodine receptor (RyR) has been identified. However, studies of isolated RyRs have mostly failed to observe alterations in the conductance of ions through the channel in the presence of clinically relevant concentrations of dantrolene. This may be the case because the ionic conditions in bilayer studies typically do not match those occurring in the muscle fibre. To examine the mechanism of dantrolene action on the RyR we used mechanically skinned fibres where the imposed ionic conditions mimic those occurring in the body. The skinned fibre allowed us to track the effect of dantrolene on Ca2+ transients in the cytoplasm elicited by action potentials; and a recently developed technique allowed the detection of the activity of the RyR under defined ionic conditions, including basal levels of activity, with a high degree of sensitivity. By varying the [Ca2+] and [Mg2+] of the cytoplasm, with and without dantrolene present, we observed that dantrolene reduced RyR activity by altering its affinity for Mg2+.