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Studies with perfused frog heart in the late 1880s led Sydney Ringer (1) first to identify the essential role of the divalent cation Ca2+ in cardiac muscle contraction. It was a landmark observation that failed to receive the immediate attention it deserved: over the following 60 or 70 years, it was followed only by a handful of scattered findings that confirmed that Ca2+, in addition to its acknowledged structural role in bones and teeth, also has a general role as a carrier of biological signals. It was not until the 1940s that this concept gained momentum with fundamental discoveries on the contraction of muscles by Heilbrunn (2) and by Bailey (3), followed subsequently by the demonstration of the active transport of Ca2+ across the membranes of the sarcoplasmic reticulum and mitochondria by Vasington and Murphy (4), DeLuca and Engstrom (5), Hasselbach and Makinose (6), and Ebashi and Lipmann (7). Ebashi's subsequent landmark discovery of troponin C (8, 9) as the calcium-binding component of the muscle protein troponin provided the molecular basis for decoding the Ca2+ message by specific binding proteins. This observation was instrumental in making Ca2+ signaling one of the most important and most intensively studied areas of cell research.
Through the decades that followed the 1960s, it became clear that Ca2+ is a major regulatory signal in all eukaryotic cells, being involved in regulating such fundamental processes as cell fertilization, movement, growth, and proliferation; neurotransmission; energy metabolism; gene transcription; and programmed cell death. The actions of calcium have been shown to be mediated by many specific, high affinity calcium-binding proteins structurally related to troponin C and by other proteins such as protein kinase C and calpain that bind and process the Ca2+ signal through distinct binding motifs. These intracellular calcium receptors are in turn regulated by elaborate systems for modulating cytosolic free calcium concentrations through the action of calcium channels that admit calcium into the cytosol and calcium pumps and translocases that remove or sequester it. Calcium transporters in the plasma membrane allow communication with the extracellular space, whereas those in internal membranes permit emptying and refilling of internal stores used for calcium signal generation.
Recent advances in elucidating the structural features of calcium channels, pumps, and translocases have provided a greater understanding of the molecular mechanisms through which the movement of Ca2+ is mediated, as well as the basis for understanding how mutations in them are linked to Ca2+ signaling disorders. The minireviews in the series entitled “Ins and Outs of Calcium Transport” will explore recent advances in understanding these structural details. A second related series entitled “Calcium Function and Disease” will explore recent advances in understanding the linkages between known calcium signaling systems and disease processes in animals.