Activating calcium release through inositol 1,4,5-trisphosphate receptors without inositol 1,4,5-trisphosphate

Cytosolic calcium (Ca²⁺) is a focal point of many signal transduction pathways and modulates a diverse array of cellular activities ranging from fertilization to cell death (1). Cells generate Ca²⁺ signals through both internal and external Ca²⁺ sources. In most cell types, the major internal Ca²⁺ stores are the endoplasmic reticulum/sarcoplasmic reticulum (ER/SR). One mechanism for mobilizing such stores involves the classical phosphoinositide pathway. Essentially, the binding of many hormones to specific receptors on the plasma membrane leads to the activation of an enzyme (phosphoinositidase C) that catalyses the hydrolysis of phospholipids to produce the intracellular messenger inositol 1,4,5-trisphosphate (InsP₃). Although derived from a lipid, InsP₃ is water soluble and diffuses into the cell interior where it encounters InsP₃ receptors (InsP₃Rs) on the ER/SR. The binding of InsP₃ changes the conformation of InsP₃Rs such that an integral channel is opened, thus allowing the Ca²⁺ stored at high concentrations in the ER/SR to enter the cytoplasm. A critical feature of InsP₃Rs is that their opening is regulated by the cytosolic Ca²⁺ concentration. This sensitivity to cytosolic Ca²⁺ allows them to act as Ca²⁺-induced Ca²⁺ release (CICR) channels that promote the rapid amplification of smaller trigger events (1).

It was thought that the binding of InsP₃ was obligatory for channel opening. However, in an elegant study in this issue of PNAS, Foskett and colleagues (2) demonstrate that a protein could supplant the need for InsP₃. Using a yeast two-hybrid screen, those authors demonstrate a high-affinity interaction between the NH₂-terminal 600 aa of an InsP₃R and a member of a previously cloned group of proteins called Ca²⁺ binding proteins (CaBPs; ref. 3). These proteins …