Thirty years of Ca²⁺ spark research: digital principle of cell signaling unveiled

Calcium ions (Ca²⁺) are an archetypical and most versatile second messenger in virtually all cell types. Inspired by the discovery of Ca²⁺ sparks in the 1990s, vibrant research over the last three decades has unveiled a constellation of Ca²⁺ microdomains as elementary events of Ca²⁺ signaling and, more importantly, a digital-analog dualism as the system design principle of Ca²⁺ signaling. In this brief review, we present a sketchy summary on advances in the field of sparkology, and discuss how the digital subsystem can fulfill physiological roles otherwise impossible for any analog system. In addition, we attempt to address how the digital-analog dualism endows the simple cation messenger with signaling speediness, specificity, efficiency, stability, and unparalleled versatility.