The foundation of excitation-contraction coupling in skeletal muscle: communication between the transverse tubules and sarcoplasmic reticulum.

The expression excitation-contraction (EC) coupling in skeletal muscle was coined in 1952 (Sandow A. 25: 176-201, 1952). The term evolved narrowly to include only the processes at the triad that intervene between depolarization of the transverse tubular (T-tubular) membrane and Ca release from the sarcoplasmic reticulum (SR). From 1970 to 1988, the foundation of EC coupling was elucidated. The channel through which Ca was released during activation was located in the SR by its specific binding to the plant insecticide ryanodine. This channel was called the ryanodine receptor (RyR). The RyR contained four subunits that together constituted the "SR foot" structure that traversed the gap between the SR and the T-tubular membrane. Ca channels, also called dihydropyridine receptors (DHPRs), were located in the T-tubular membrane at the triadic junction and shown to be essential for EC coupling. There was a precise relationship between the two channels. Four DHPRs, organized as tetrads, were superimposed on alternate RyRs. This structure was consistent with the proposal that EC coupling was mediated via a movement of intramembrane charge in the T-tubular system. The speculation was that the DHPR acted as a voltage sensor transferring information to the RyRs of the SR by protein-protein interaction causing the release of Ca from the SR. A great deal of progress was made by 1988 toward understanding EC coupling. However, the ultimate question of how voltage sensing is coupled to the opening of the SR Ca release channel remains unresolved. The least understood part of the series of events in excitation-contraction coupling in skeletal muscle was how information was transmitted from the transverse tubules to the sarcoplasmic (SR) and how Ca was released from the SR. Through an explosion of technical approaches including physiological, biochemical, structural, pharmacological, and molecular genetics, much was discovered between 1970 and 1988. By the end of 1988, the foundation of EC coupling in skeletal muscle was established.