G protein-coupled receptors (GPCRs) are cell surface receptors that detect a 
wide range of extracellular messengers and convey this information to the inside 
of cells. Extracellular calcium-sensing receptor (CaSR) and ovarian cancer gene 
receptor 1 (OGR1) are two GPCRs that sense extracellular Ca(2+) and H(+), 
respectively. These two ions are key components of the interstitial fluid, and 
their concentrations change in an activity-dependent manner. Importantly, the 
interstitial fluid forms part of the microenvironment that influences cell 
function in health and disease; however, the exact mechanisms through which 
changes in the microenvironment influence cell function remain largely unknown. 
We show that CaSR and OGR1 reciprocally inhibit signaling through each other in 
central neurons, and that this is lost in their transformed counterparts. 
Furthermore, strong intracellular acidification impairs CaSR function, but 
potentiates OGR1 function. Thus, CaSR and OGR1 activities can be regulated in a 
seesaw manner, whereby conditions promoting signaling through one receptor 
simultaneously inhibit signaling through the other receptor, potentiating the 
difference in their relative signaling activity. Our results provide insight 
into how small but consistent changes in the ionic microenvironment of cells can 
significantly alter the balance between two signaling pathways, which may 
contribute to disease progression.