Altered transverse tubule dihydropyridine receptor binding in malignant hyperthermia

Transverse tubule (TT) membrane vesicles have been isolated from the skeletal muscle of normal and malignant hyperthermia-susceptible (MHS) pigs. MHS and normal TT did not differ in the distribution of the major proteins, cholesterol, or phospholipid content, (Na⁺ + K⁺)-ATPase activity, [³H]ouabain binding, Ca²⁺-ATPase activity, Mg²⁺-ATPase activity, or [³H]saxitoxin binding. Furthermore, in the presence of micromolar Ca²⁺, MHS and normal TT did not differ significantly in the K(D) values for either [³H]nitrendipine binding (2.7 ± 0.6 and 3.3 ± 0.5 nM, respectively) or (-)-[³H]desmethoxyverapamil ([³H]D888) binding (7.2 ± 0.9 and 6.4 ± 0.6 nM, respectively). However, in contrast to normal TT, MHS TT exhibited a significantly decreased B(max) for both [³H]nitrendipine binding (26.4 ± 5.4 for MHS versus 40.6 ± 3.7 pmol/mg protein for normal TT) and [³H]D888 binding (17.8 ± 7.0 for MHS versus 37.4 ± 5.9 pmol/mg protein for normal TT). At calcium concentrations greater than 0.1 mM, there was a greater inhibition of [³H]nitrendipine binding to normal than to MHS TT such that binding was now similar for both preparations. As with purified TT, [³H]nitrendipine binding to MHS muscle homogenates was significantly less than to normal muscle homogenates (109 ± 20 versus 211 ± 19 pmol/mg protein, for MHS and normal TT, respectively); this difference was not apparent when 100 mM CaCl₂ was included in the binding medium. We conclude that the altered MHS TT dihydropyridine receptor properties may reflect an adaptation of the TT voltage sensing mechanism to the abnormal sarcoplasmic reticulum calcium release channel regulation in MHS muscle.