Elevated resting [Ca2+]i in myotubes expressing malignant hyperthermia RyR1 cDNAs is partially restored by modulation of passive calcium leak from the SR

Tianzhong Yang, Eric Esteve, Isaac N Pessah, Tadeusz F. Molinski, Paul D. Allen, José R. López

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Abstract

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle triggered in susceptible individuals by inhalation anesthetics and depolarizing skeletal muscle relaxants. This syndrome has been linked to a missense mutation in the type 1 ryanodine receptor (RyR1) in more than 50% of cases studied to date. Using double-barreled Ca2+ microelectrodes in myotubes expressing wild-type RyR1 (WTRyR1) or RyR1 with one of four common MH mutations (MHRyR1), we measured resting intracellular Ca2+ concentration ([Ca2+]i). Changes in resting [Ca2+]i produced by several drugs known to modulate the RyR1 channel complex were investigated. We found that myotubes expressing any of the MHRyR1s had a 2.0- to 3.7-fold higher resting [Ca2+]i than those expressing WTRyR1. Exposure of myotubes expressing MHRyR1s to ryanodine (500 μM) or (2,6-dichloro-4-aminophenyl)isopropylamine (FLA 365; 20 μM) had no effects on their resting [Ca2+]i. However, when myotubes were exposed to bastadin 5 alone or to a combination of ryanodine and bastadin 5, the resting [Ca2+]i was significantly reduced (P < 0.01). Interestingly, the percent decrease in resting [Ca2+]i in myotubes expressing MHRyR1s was significantly greater than that for WTRyR1. From these data, we propose that the high resting myoplasmic [Ca2+]i in MHRyR1 expressing myotubes is due in part to a related structural conformation of MHRyR1s that favors "passive" calcium leak from the sarcoplasmic reticulum.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume292
Issue number5
DOIs
StatePublished - May 2007

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Keywords

  • Bastadin 5
  • FLA 365
  • Resting intracellular calcium concentration
  • Ryanodine
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

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