Calcium ions as extracellular messengers

The capacity to regulate their internal ionic composition is a fundamental property of free-living terrestrial organisms (Stewari and Broadus, 1987). This is accomplished by adjusting the movement of ions or water (or both) between cells and various extracellular compartments, including those communicating with the external environment. Of the complement of inorganic ions in such organisms, Ca2+ performs an especially large number of intracellular and extracellular functions. It is a well-known intracellular second messenger, controlling numerousvital processes(see minireview by Bootman and Berridge, 1995 [this issue of Ce//]). The cytosolic free Ca2+ concentration ([CaZ+li) undergoes rapid and often substantial (i.e., severalfold or more) fluctuations in response to extracellular first messengers binding to their cognate receptors on target cells. The extracellular ionized Ca2+ concentration ([CaZ+lO), in contrast, is maintained stably at 1 mM, at least lO,OOOfold higher than the resting level of [Ca2+li in most cells, providing a seemingly inexhaustible supply of Ca2+ for its diverse intracellular functions. Caz+ is also an essential component or cofactor in key extracellular structures or processes (i.e., bone, clotting factors, and adhesion molecules) whose biological functions could be compromised by large changes in [Ca2+10, with potentially disastrous consequences. It is not intuitively obvious, therefore, that Ca2+ serves as an important extracellular first messenger. The recent cloning of an extracellular CaZ+-sensing receptor (CaR), however, has firmly established that [Ca2+],, serves such an informational role (Brown et al., 1993). This minireview will briefly outline the signaling function of [Ca2+10, particularly the role of [CaQsensing mechanisms within various extracellular compartments in this process. The [Ca2+], Signal For extracellular Ca2+ to serve an informational role, it must undergo sufficiently large perturbations to be recognized by [Ca2+],-sensing mechanisms (or the responsiveness of the latter must change). In mammals, blood-ionized Ca*+ varies by only a few percent over the course of a day or even much of a lifetime. This remarkable stability of [CaZ+], results from a homeostatic system with two principal elements: [CaZ+],-sensing cells (e.g., parathyroid cells) and tissues that respond to either local or systemic signals from these [Ca2+],-sensing cells by altering their translocation of Ca2+ into or out of the extracellular fluid (i.e., kidney, intestine, and bone) (Stewart and Broadus, 1987). The near constancy of the blood-ionized CaZ+ concentration underscores the exquisite responsiveness of [Ca2+10Minireview