Biochemical studies have cloned, isolated and sequenced the Na+ and other ion channels in their related protein family; cryo-electronmicroscopic structural determinations have characterised details of their structure. Biophysical measurements of intramembrane charge movement provided electrical signatures clarifying the dynamics and mechanisms of the channel conformational responses to membrane voltage change. Such charge movements were demonstrated, studied and quantified in a wide range of ion-channel species and cell types. Finally, radioactive tracer flux experiments examined the basis for their ion selectivity and permeation. Together these detailed characterisations separated and clarified the mechanisms for ion channel gating and channel permeability to specific ions. They identified voltage-sensing modules and how each domain contributed to the ion-specific pore module within each domain of the four-domain structure making up the ion-channel protein. These studies thus together provide a continuing clarification of the molecular basis through which ion channels mediate excitability in biological membranes.

Excitation-contraction coupling refers to the events connecting surface membrane excitation and initiation of mechanical activity. It involves a steeply voltage-dependent Ca2+ release from its intracellular sarcoplasmic reticular store. The resulting cytosolic Ca2+ elevation, leading to troponin activation, is detectable through absorbance or fluorescence properties of intracellularly introduced optically sensitive dyes. The initiating transverse tubular depolarisation is sensed by intramembrane dihydropyridine receptors at triad junctions with terminal cisternal sarcoplasmic reticulum. Their underlying configurational changes were demonstrated and characterised through their associated intramembrane charge movements employing pharmacological agents known to modify excitation-contraction coupling. This separated a steeply voltage-dependent qγ transition allosterically and co-operatively coupled to opening of sarcoplasmic reticular ryanodine receptor Ca2+ release channels. These events and the associated Ca2+ release reverse with membrane repolarisation. Sarcoplasmic reticular Ca2+-ATPase activity then returns the released Ca2+ from cytosol to its sarcoplasmic reticular store. Clinical ryanodine receptor disorders cause malignant hyperthermia, important in anaesthetic practice.