Extracellular calcium as an integrator of tissue function

The past several decades of research into calcium signaling have focused on intracellular calcium (Cai2+), revealing both exquisite spatial and dynamic control of this potent second messenger. Our understanding of Cai2+ signaling has benefited from the evolution of cell culture methods, development of high affinity fluorescent calcium indicators (both membrane-permeant small molecules and genetically encoded proteins), and high-resolution fluorescence microscopy. As our understanding of single cell calcium dynamics has increased, translational efforts have attempted to push calcium signaling studies back into tissues, organs and whole animals. Emerging results from these more complicated, diffusion-limited systems have begun to define a role for extracellular calcium (Cao2+) as an agonist, spurred by the cloning and characterization of a G protein-coupled receptor activated by Cao2+ (the calcium sensing receptor, CaR). Here, we review the current state-of-the art for measurement of Cao2+ fluctuations, and the evidence that fluctuations in Cao2+ can act as primary signals regulating cell function. Current results suggest that Cao2+ in bone and epidermis may act as a chemotactic homing signal, targeting cells to the appropriate tissue locations prior to initiation of the differentiation program. Cai2+ signaling-mediated Cao2+ fluctuations in interstitial spaces may integrate cell signaling responses in multicellular networks through activation of CaR. Appreciation of the importance of Cao2+ fluctuations in coordinating cell function will likely spur identification of additional, niche-specific Ca2+ sensors, and provide unique insights into the regulation of multicellular signaling networks.