Ca2+ influx via the Na+/Ca2+ exchanger is enhanced in malignant hyperthermia skeletal muscle.
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.
From the Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616.
Francisco
F
Altamirano
the Department of Anesthesiology Perioperative and Pain Medicine, Brigham & Women's Hospital, Boston, Massachusetts 02115, and the Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia 23298.
José M
JM
Eltit
From the Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616.
Gaëlle
G
Robin
the Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Caracas 1020-A, Venezuela.
Nancy
N
Linares
the Department of Anesthesiology Perioperative and Pain Medicine, Brigham & Women's Hospital, Boston, Massachusetts 02115, and.
Xudong
X
Ding
From the Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616.
Isaac N
IN
Pessah
From the Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616, the Department of Anesthesiology Perioperative and Pain Medicine, Brigham & Women's Hospital, Boston, Massachusetts 02115, and.
Paul D
PD
Allen
From the Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616, the Department of Anesthesiology Perioperative and Pain Medicine, Brigham & Women's Hospital, Boston, Massachusetts 02115, and the Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Caracas 1020-A, Venezuela, jrlopez@ucdavis.edu.
José R
JR
López
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006221:Halothane / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008305:Malignant Hyperthermia / Q000378:metabolism* / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*; D013552:Swine; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; C516554:N-(3-aminobenzyl)-6-(4-((3-fluorobenzyl)oxy)phenoxy)nicotinamide; D019831:Sodium-Calcium Exchanger; D009536:Niacinamide; D012964:Sodium; D013890:Thiourea; D011188:Potassium; D002118:Calcium; D006221:Halothane
Calcium Imaging; Calcium Signaling; KB-R7943; Malignant Hyperthermia; Skeletal Muscle; Sodium-Calcium Exchange; YM-244769