The nuts and bolts of excitation–contraction coupling in skeletal muscle

Mobility in humans and all animals depends on the co-ordinated progress of essential steps linking electrical action potentials along the surface membrane of muscle fibres to the increased cytoplasmic Ca 2+ concentrations that activate the contractile proteins. Excitation–contraction (EC) coupling is the transformation of an electrical signal into a massive release of Ca 2+ from intracellular Ca 2+ stores. We consider the evolution of our knowledge of the structures and proteins that underlie skeletal muscle EC coupling, unanswered questions and future developments that will reveal the fundamental molecular events of the coupling process. The deeper understanding gained with future developments will reveal the molecular basis of muscle weakness related to mutations in EC coupling proteins or result from fatigue and aging. The benefits will flow on to the rational design of therapies to increase muscle strength in the many situations where muscle weakness is related to changes in EC coupling.