title: Impaired gating of an L-Type Ca(2+) channel carrying a mutation linked to malignant hyperthermia.
abstract: Recently, we characterized the functional properties of a mutant skeletal muscle L-type Ca(2+) channel (CaV1.1 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 CaV1.1, 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 CaV1.1 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 CaV1.1 R174W will open and conduct Ca(2+) 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 Po) and mode 2 (high Po) gating states and that these gating impairments can be partially overcome by maneuvers that promote entry into mode 2.
authors.affiliation: Department of Medicine, Cardiology Division, University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado, USA. roger.bannister@ucdenver.edu
authors.forename: Roger A
authors.initials: RA
authors.lastname: Bannister
authors.forename: Kurt G
authors.initials: KG
authors.lastname: Beam
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000235:genetics* / Q000378:metabolism*; D015640:Ion Channel Gating / Q000235:genetics*; D008305:Malignant Hyperthermia / Q000235:genetics*; D008564:Membrane Potentials; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000502:physiology; D020125:Mutation, Missense
chemical_list: C529218:CACNA1S protein, mouse; D002120:Calcium Channel Agonists; D020746:Calcium Channels, L-Type; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D002118:Calcium