The extracellular calcium-sensing receptor and cell–cell signaling in epithelia

In multicellular organisms, cells are crowded together in organized communities, surrounded by an interstitial fluid of extremely limited volume. Local communication between adjacent cells is known to occur through gap junctions in cells that are physically connected, or through the release of paracrine signaling molecules (e.g. ATP, glutamate, nitric oxide) that diffuse to their target receptors through the extracellular microenvironment. Recent evidence hints that calcium ions may possibly be added to the list of paracrine messengers that allow cells to communicate with one another. Local fluctuations in extracellular [Ca 2+] can be generated as a consequence of intracellular Ca 2+ signaling events, owing to the activation of Ca 2+ influx and efflux pathways at the plasma membrane. In intact tissues, where the interstitial volumes between cells are much smaller than the cells themselves, this can result in significant alterations in external [Ca 2+]. This article will explore emerging evidence that these extracellular [Ca 2+] changes can be detected by the extracellular calcium-sensing receptor (CaR) on adjacent cells, forming the basis for a paracrine signaling system. Such a mechanism could potentially provide CaR-expressing cells with the means to sense the Ca 2+ signaling status of their neighbors, and expand the utility of the intracellular Ca 2+ signal to a domain outside the cell.