CAFFEINE STIMULATION OF MALIGNANT HYPERTHERMIA-SUSCEPTIBLE SARCOPLASMIC-RETICULUM CA2+ RELEASE CHANNEL

The altered caffeine sensitivity of malignant hyperthermia-susceptible (MHS) muscle contracture is one basis of the diagnostic test for this syndrome. To determine whether the Arg(615)-to-Cys(615) mutation of t he porcine sarcoplasmic reticulum (SR) Ca2+ release channel is directl y responsible for this altered caffeine sensitivity, the single-channe l kinetics of purified MHS and normal pig Ca2+ release channels were e xamined. Initial studies demonstrated that decreasing the pH of the me dium in either the cis- or trans-chamber decreased the Ca2+ release ch annel percent open time (P-o). The half-inhibitory pH of MHS channels (6.86 +/- 0.04, n = 17) was significantly different from that of norma l channels (7.08 +/- 0.07, n = 14). At pH 7.4, in either 7 or 0.12 mu M Ca2+, MHS channel P-o was not significantly different from that of n ormal channels over the range 0-10 mM caffeine. Although at pH 6.8 in 7 mu M Ca2+ MHS channel P-o was greater than that of normal channels o ver the range 0-20 mM caffeine, the difference could be eliminated by dividing each mean MHS P-o by a scaling factor of 3.2. Thus the MHS Ca 2+ release channel mutation does not appear to be directly responsible for the altered caffeine sensitivity of MHS pig muscle contracture. R ather, this altered caffeine sensitivity may result from an altered re sting myoplasmic Ca2+ concentration or the altered pH and Ca2+ sensiti vity of Ca2+ release channel P-o of MHS muscle.