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National Institute of Environmental Health Sciences

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Publication Detail

Title: Ca2+ influx via the Na+/Ca2+ exchanger is enhanced in malignant hyperthermia skeletal muscle.

Authors: Altamirano, Francisco; Eltit, José M; Robin, Gaëlle; Linares, Nancy; Ding, Xudong; Pessah, Isaac N; Allen, Paul D; López, José R

Published In J Biol Chem, (2014 Jul 04)

Abstract: Malignant hyperthermia (MH) is potentially fatal pharmacogenetic disorder of skeletal muscle caused by intracellular Ca(2+) dysregulation. NCX is a bidirectional transporter that effluxes (forward mode) or influxes (reverse mode) Ca(2+) depending on cellular activity. Resting intracellular calcium ([Ca(2+)]r) and sodium ([Na(+)]r) concentrations are elevated in MH susceptible (MHS) swine and murine muscles compared with their normal (MHN) counterparts, although the contribution of NCX is unclear. Lowering [Na(+)]e elevates [Ca(2+)]r in both MHN and MHS swine muscle fibers and it is prevented by removal of extracellular Ca(2+) or reduced by t-tubule disruption, in both genotypes. KB-R7943, a nonselective NCX3 blocker, reduced [Ca(2+)]r in both swine and murine MHN and MHS muscle fibers at rest and decreased the magnitude of the elevation of [Ca(2+)]r observed in MHS fibers after exposure to halothane. YM-244769, a high affinity reverse mode NCX3 blocker, reduces [Ca(2+)]r in MHS muscle fibers and decreases the amplitude of [Ca(2+)]r rise triggered by halothane, but had no effect on [Ca(2+)]r in MHN muscle. In addition, YM-244769 reduced the peak and area under the curve of the Ca(2+) transient elicited by high [K(+)]e and increased its rate of decay in MHS muscle fibers. siRNA knockdown of NCX3 in MHS myotubes reduced [Ca(2+)]r and the Ca(2+) transient area induced by high [K(+)]e. These results demonstrate a functional NCX3 in skeletal muscle whose activity is enhanced in MHS. Moreover reverse mode NCX3 contributes to the Ca(2+) transients associated with K(+)-induced depolarization and the halothane-triggered MH episode in MHS muscle fibers.

PubMed ID: 24847052 Exiting the NIEHS site

MeSH Terms: Animals; Calcium/metabolism*; Extracellular Space/drug effects; Extracellular Space/metabolism; Gene Knockdown Techniques; Halothane/pharmacology; Intracellular Space/drug effects; Intracellular Space/metabolism; Malignant Hyperthermia/metabolism*; Malignant Hyperthermia/pathology; Membrane Potentials/drug effects; Mice; Muscle Fibers, Skeletal/drug effects; Muscle Fibers, Skeletal/metabolism; Muscle Fibers, Skeletal/pathology; Muscle, Skeletal/metabolism*; Muscle, Skeletal/pathology; Niacinamide/analogs & derivatives; Niacinamide/pharmacology; Potassium/metabolism; Sodium-Calcium Exchanger/genetics; Sodium-Calcium Exchanger/metabolism*; Sodium/metabolism; Swine; Thiourea/analogs & derivatives; Thiourea/pharmacology

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