Regulation of Intracellular Free Calcium

It can be argued that the calcium ion is the oldest recognized signal transduction molecule, whether one dates the birth of this recognition with Ringer’s 1883 studies1 on the requirement for extracellular Ca2+ in myocardial contraction, or with Heilbrunn’s much later proposal2 that Ca2+ is the physiological inducer of muscle contraction. Perhaps because of this early focus on calcium’s role in contractility in particular, and in the function of classically “excitable” cells generally (such as Katz and Miledi’s seminal studies on the role of Ca2+ in neurotransmitter release3), the first 100 years of cell calcium research was dominated by efforts to understand how transient changes in intracellular free Ca2+ activity ([Ca2+]i) are achieved and transduced in but two very specialized cell types—muscle and neuron.