title: Accelerated activation of SOCE current in myotubes from two mouse models of anesthetic- and heat-induced sudden death.
abstract: Store-operated calcium entry (SOCE) channels play an important role in Ca(2+) signaling. Recently, excessive SOCE was proposed to play a central role in the pathogenesis of malignant hyperthermia (MH), a pharmacogenic disorder of skeletal muscle. We tested this hypothesis by characterizing SOCE current (ISkCRAC) magnitude, voltage dependence, and rate of activation in myotubes derived from two mouse models of anesthetic- and heat-induced sudden death: 1) type 1 ryanodine receptor (RyR1) knock-in mice (Y524S/+) and 2) calsequestrin 1 and 2 double knock-out (dCasq-null) mice. ISkCRAC voltage dependence and magnitude at -80 mV were not significantly different in myotubes derived from wild type (WT), Y524S/+ and dCasq-null mice. However, the rate of ISkCRAC activation upon repetitive depolarization was significantly faster at room temperature in myotubes from Y524S/+ and dCasq-null mice. In addition, the maximum rate of ISkCRAC activation in dCasq-null myotubes was also faster than WT at more physiological temperatures (35-37°C). Azumolene (50 µM), a more water-soluble analog of dantrolene that is used to reverse MH crises, failed to alter ISkCRAC density or rate of activation. Together, these results indicate that while an increased rate of ISkCRAC activation is a common characteristic of myotubes derived from Y524S/+ and dCasq-null mice and that the protective effects of azumolene are not due to a direct inhibition of SOCE channels.
authors.affiliation: Department of Physiology and Pharmacology, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Viktor
authors.initials: V
authors.lastname: Yarotskyy
authors.forename: Feliciano
authors.initials: F
authors.lastname: Protasi
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dirksen
mesh_terms: D000054:Acceleration; D000777:Anesthetics / Q000009:adverse effects*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000235:genetics; D002155:Calsequestrin / Q000172:deficiency / Q000235:genetics; D003645:Death, Sudden / Q000209:etiology*; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D055879:Gene Knock-In Techniques; D055786:Gene Knockout Techniques; D006358:Hot Temperature / Q000009:adverse effects*; D007093:Imidazoles / Q000009:adverse effects; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010080:Oxazoles / Q000009:adverse effects; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics
chemical_list: D000777:Anesthetics; D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D002155:Calsequestrin; C503130:Casq1 protein, mouse; D007093:Imidazoles; D010080:Oxazoles; D019837:Ryanodine Receptor Calcium Release Channel; C514388:casq2 protein, mouse; C061387:azumolene; D002118:Calcium