Calcium-sensing receptor signaling: it's all about multiplicity

The Calcium-Sensing Receptor (CaSR), a G-protein-coupled receptor mainly known for its role in the homeostatic regulation of Ca2+ levels in the extracellular fluid, is also expressed in a multiplicity of tissues where it regulates a variety of physiological and pathological processes. The main features of CaSR are its capacity to activate multiple downstream signaling pathways and its ability to itself be activated by a variety of ligands. Recent data have demonstrated that these features are actually connected by the concept of biased signaling. The recent availability of crystal structures of CaSR extracellular domain, and the functional characterization of clinically relevant mutations, have catalyzed a great step forward in the field of CaSR signaling. In the past two years, CaSR signaling characteristics have been shown to be even more complicated than expected: heterodimerization, phosphate-sensing, and compartment bias are only a fraction of the exciting developments. This review will focus on some of these topics, and on the debated case of CaSR signaling in cardiomyocytes.