Control of calcium in skeletal muscle excitation-contraction coupling: implications for malignant hyperthermia

The missing link in our understanding of excitation-contraction coupling (ECC) in skeletal muscle is the mechanism by which Ca2+ increases in the cytosol to trigger contraction. We discuss here a general background of intracellular Ca2+ handling, some characteristics of the major proteins involved in Ca2+ flow during ECC, and mechanisms currently believed to explain the increase in Ca2+ upon stimulation of muscle cells. These mechanisms include the calcium-induced calcium release, the direct coupled mechanism in which a plasma membrane and sarcoplasmic reticulum membrane protein interact, and mechanisms involving Ca2+ secretagogues that are known to elicit increases in calcium in other cells, inositol trisphosphate, and cyclic ADP ribose. We also consider possible roles for proteins associated with the principal calcium release channel of the sarcoplasmic reticulum, the ryanodine receptor. Finally, we discuss malignant hyperthermia, a disease associated directly with aberrant control of muscle cell calcium release.