The action of perchlorate on malignant-hyperthermia-susceptible muscle

Abstract

To better understand the altered skeletal muscle excitation-contraction (E-C) coupling that occurs in malignant hyperthermia, we have examined the potentiating actions of perchlorate in intact muscle fiber bundles, isolated sarcoplasmic reticulum (SR) vesicles, and the purified ryanodine receptor/Ca2+ release channel (RyR) isolated from malignant-hyperthermia-susceptible (MHS) and normal porcine muscle. The concentration of perchlorate that half-maximally potentiated twitch tension (2.5-3.5 mM) was not significantly different for MHS and normal muscles. The effect of perchlorate on fractional twitch force was significantly greater for normal than for MHS muscle, although the absolute twitch potentiation was similar for both muscle types. The K-contracture threshold of MHS muscle bundles is significantly lower than that of normal bundles; perchlorate shifted the K-contraction activation curves of both MHS and normal muscle bundles to lower K+ concentrations. Perchlorate both increased ryanodine binding to MHS and normal SR vesicles and increased single-channel open probability of the purified MHS and normal RyR. In both cases, the percentage increase was greater for normal than for MHS preparations; however, the absolute increase in activity was not different for MHS and normal RyR indicating that there is no difference in the perchlorate sensitivity of MHS and normal SR Ca2+ release channels. Thus, the greater absolute responses of the MHS Ca2+ release channel in the presence of perchlorate is likely to be due to the greater basal activity of the MHS release channel and does not reflect an underlying defect in the site of action of perchlorate on the MHS skeletal muscle Ca2+ release channel.

Voltage modulates halothane-triggered Ca2+ release in malignant hyperthermia-susceptible muscle

“…In addition, or alternatively, the coupling process itself might be changed as in the case of the chaotropic anion perchlorate. This substance likewise shifts the voltage dependence of activation ( Gomolla et al, 1983 ; Lüttgau et al, 1983 ; González and Ríos, 1993 ; Csernoch et al, 1999 ) by affecting the ryanodine receptor ( Ma et al, 1993 ; Anderson et al, 1997 ). However, it also increases the sensitivity of Ca 2+ release to the voltage sensor input signal, reflected in an alteration of the “transfer function,” i.e., the relationship between voltage sensor charge movement and Ca 2+ release ( González and Ríos, 1993 ; Ma et al, 1993 ; Ríos et al, 1993 , 2015 ; Csernoch et al, 1999 ).…”

“…A direct comparison of both drugs in mammalian muscle revealed differences in their transfer functions ( Csernoch et al, 1999 ), indicating that they alter EC coupling in different ways. The effects of both caffeine and perchlorate have also been compared in WT versus MHS preparations by studying ryanodine receptor open probability and potassium-induced contractures ( Anderson et al, 1997 ). The alterations in voltage dependence resembled our result of Fig.…”