LAUSR

Calcium’s importance in signaling has been known since Ringer showed that it was needed for contraction of isolated hearts in 1883. Calcium remained a curiosity until the mid 1940s when Heilbrunn showed that intracellular calcium is the trigger for muscle contraction (1). Since then, calcium has been implicated in so many cellular processes, some have wondered how one ion can do so many things. The large difference in calcium concentration between the cytoplasm (∼0.1 μM), the intracellular organelles (400 μM), and the extracellular fluid (1.5 mM) allows small fluxes of calcium to have a big impact. But there are several features of the intracellular calcium signaling network that make it possible for this one ion to invoke specific responses within the cell. Two of these properties are the location of the calcium release into the cytoplasm and the location at which calcium itself binds and regulates components of the signaling complex. In PNAS, Arige et al. (2) identify a critical calcium binding site on the inositol trisphosphate receptor (IP3R), a major component of calcium signaling that addresses both aspects of location. The mammalian IP3R has three isoforms, and, although remarkably similar, each isoform has unique cellular locations and properties. Even though most mammalian cells express all three isoforms, the primary IP3R isoform expressed differs among cell types. For example, cerebellar Purkinje cells express primarily InsP3R type 1 (IP3R1), and hepatocytes express primarily InsP3R type 2 (IP3R2) (3–5). Additionally, isoforms are found in distinct subcellular locations. In pancreatic acinar cells, IP3R2 is found near the apical end of the cell, providing a barrier to calcium transients invading the secretory end of the cell (6), and IP3R3 and IP3R1 are localized to regions where the mitochondria and endoplasmic reticulum (ER) meet (mitochondrial-associated membrane; e.g., refs. 7–9) to enhance calcium flow between these two organelles. These subcellular locations and the type of IP3Rs at specific sites can be changed by disease (7, 10, 11).