Impaired Gating of an L-Type Ca2+ Channel Carrying a Mutation Linked to Malignant Hyperthermia

Recently, we characterized the functional properties of a mutant skeletal muscle L-type Ca2+ channel (Ca(v)1.1 R174W) linked to the pharmacogenetic disorder malignant hyperthermia. Although the R174W mutation neutralizes the innermost basic amino acid in the voltage-sensing S4 helix of the first conserved membrane repeat of Ca(v)1.1, the ability of the mutant channel to engage excitation-contraction coupling was largely unaffected by the introduction of the bulky tryptophan residue. In stark contrast, the mutation ablated the ability of Ca(v)1.1 to produce L-type current under our standard recording conditions. In this study, we have investigated the mechanism of channel dysfunction more extensively. We found that Ca(v)1.1 R174W will open and conduct Ca2+ in response to strong or prolonged depolarizations in the presence of the 1,4-dihydropyridine receptor agonist +/- Bay K 8644. From these results, we have concluded that the R174W mutation impedes entry into both mode 1(low P-o) and mode 2 (high P-o) gating states and that these gating impairments can be partially overcome by maneuvers that promote entry into mode 2.