[High resolution fluorescence microscopy in combination with mathematical modelling. First evidence of sub-cellular...

Volatile anesthetics used in daily clinical routine, are associated with a rare but life-threatening disease, malignant hyperthermia. To date it is well known that, with the exception of xenon and nitrous oxide, all volatile anesthetics have the potential to trigger calcium (Ca(2+)) release from the sarcoplasmic reticulum, thereby influencing the Ca(2+) homeostasis in muscle fibers. The effects of volatile anesthetics have been previously studied by recording Ca(2+)-activated force transients in muscle fibers and by quantifying the effects on isolated intracellular Ca(2+)-release channels (ryanodin receptors). The use of high resolution fluorescence microscopy methods in combination with spatio-temporal mathematical models allows the effects of volatile anesthetics on functional clusters of ryanodin receptors in mammalian skeletal muscle fibers to be studied in situ for the first time.Thus, the analysis of cellular Ca(2+)-activated force production and single channel properties in conjunction with mathematical models allows the quantification of the effects of volatile anesthetics on Ca(2+)-release in the natural physiological environment on the basis of the underlying molecular architecture. In addition to the basic understanding of alterations in the Ca(2+) homeostasis induced by volatile anesthetics in muscle and nerve cells, the results are also of direct clinical importance for the understanding of the pathogenesis of malignant hyperthermia,where ryanodin receptor mutations are currently thought to result in an increased Ca(2+) release under the influence of volatile anesthetics.