Malignant hyperthermia and calcium-induced heat production

The abnormal increase in intracellular Ca++ in malignant hyperthermia (MH) is well documented, but the link between the increased Ca++ concentration and high temperature remains speculative. We investigated the possibility that the Ca(++)-induced change in the state of cell membranes may contribute to the temperature elevation. Calcium ion transforms phospholipid membranes from the fluid to solid state. This is analogous to the freezing of water, and liberates latent heat. Differential titration calorimetry (DTC) measures heat production or absorption during ligand binding to macromolecules. When CaCl2 solution was added to anionic dimyristoylphosphatidic acid (DMPA) and dimyristoylphosphatidylglycerol (DMPG) vesicle membranes in incremental doses, DTC showed that the heat production suddenly increased when the Ca++ concentration exceeded about 120 microM. At this Ca++ concentration range, these lipid membranes underwent phase transition. The latent heat of transition was measured by differential scanning calorimetry (DSC). The values were 7.1 +/- 0.7 (SD, n = 4) kcal.mol-1 of DMPA and 6.8 +/- 0.7 (SD, n = 4) kcal.mol-1 of DMPG. The study shows that Ca++ produces heat when bound to lipid membranes. We are not proposing, however, that this is the sole source of heat. We contend that the lipid phase transition is one of the heat sources and it may trigger a hypermetabolic state by elevating the temperature of cell membranes. Because Ca++ is implicated as the second messenger in signal transduction, multiple systems may be involved. More studies are needed to clarify how Ca++ increases body temperature.