Ca(2+) Channels Mediate Bidirectional Signaling between Sarcolemma and Sarcoplasmic Reticulum in Muscle Cells

The skeletal muscle and myocardial cells present highly specialized structures; for example, the close interaction between the sarcoplasmic reticulum (SR) and mitochondria—responsible for excitation-metabolism coupling—and the junction that connects the SR with T-tubules, critical for excitation-contraction (EC) coupling. The mechanisms that underlie EC coupling in these two cell types, however, are fundamentally distinct. They involve the differential expression of Ca(2+) channel subtypes: Ca(V)1.1 and RyR1 (skeletal), vs. Ca(V)1.2 and RyR2 (cardiac). The Ca(V) channels transform action potentials into elevations of cytosolic Ca(2+), by activating RyRs and thus promoting SR Ca(2+) release. The high levels of Ca(2+), in turn, stimulate not only the contractile machinery but also the generation of mitochondrial reactive oxygen species (ROS). This forward signaling is reciprocally regulated by the following feedback mechanisms: Ca(2+)-dependent inactivation (of Ca(2+) channels), the recruitment of Na(+)/Ca(2+) exchanger activity, and oxidative changes in ion channels and transporters. Here, we summarize both well-established concepts and recent advances that have contributed to a better understanding of the molecular mechanisms involved in this bidirectional signaling.