Reciprocal regulation of two G protein-coupled receptors sensing extracellular concentrations of Ca 2+ and H +

Significance The composition of the extracellular fluid surrounding all cells changes in an activity-dependent manner. Cell surface receptors allow cells to respond to components of the fluid, which is vital for proper functioning of cells and tissues. Ca 2+ and H + are crucial for cell survival and functioning. Their extracellular concentrations are monitored by two receptors, extracellular calcium-sensing receptor (CaSR) and ovarian cancer gene receptor 1 (OGR1), respectively. We report that these two receptors can be regulated in a seesaw manner; conditions favoring activity of one receptor inhibit signaling through the other, and vice versa, allowing cells to detect subtle changes in the extracellular concentration of these ions. We provide evidence that dysregulated activity of CaSR and OGR1 may contribute to the formation and progression of pathologies.