Abstract: | Calcium ions are Nature's most widely used signaling mechanism, mediating communication between pathways at virtually every physiological level. Ion channels are no exception, as the activities of a wide range of ion channels are intricately shaped by fluctuations in intracellular Ca2+ levels. Mirroring the importance and the breadth of Ca2+ signaling, free Ca2+ levels are tightly controlled, and a myriad of Ca2+ binding proteins transduce Ca2+ signals, each with its own nuance, comprising a constantly changing symphony of metabolic activity. The founding member of Ca2+ binding proteins is calmodulin (CaM), a small, acidic, modular protein endowed with gymnastic-like flexibility and E-F hand motifs that chelate Ca2+ ions. In this review, I will trace the history that led to the realization that CaM serves as the Ca2+-gating cue for SK channels, the experiments that revealed that CaM is an intrinsic subunit of SK channels, and itself a target of regulation. |