Acidic extracellular pH-induced PTH secretion in male mouse parathyroids is OGR1-dependent

The role of extracellular acidity in regulating PTH secretion in cultured mouse parathyroid glands (PTGs) has not been studied to date, largely because of the technical difficulty of isolating mouse PTGs. We hypothesized that acidic extracellular pH directly stimulates PTH secretion through activation of a proton-sensing receptor, specifically ovarian cancer G protein-coupled receptor 1 (OGR1, also known as GPR68). To test this, we developed a method to reliably identify and isolate PTGs from male mice by administering 5-aminolevulinic acid, which induced selective fluorescence in these glands. Using this model, we demonstrate that acidic extracellular pH significantly stimulates PTH secretion in cultured mouse PTGs. Mechanistically, we identify OGR1 as the primary proton sensor mediating this response, as PTGs from OGR1 knockout mice failed to increase PTH secretion under acidic conditions, with no evidence of compensatory upregulation of other proton-sensing receptors. In addition, we found that low extracellular Ca2+ not only stimulates PTH secretion but also promotes extracellular acidification. Notably, low Ca2+ and acidic pH act synergistically to enhance PTH secretion in wild-type PTGs, an effect markedly attenuated in OGR1-deficient glands. Together, these findings establish a direct, OGR1-dependent mechanism by which extracellular acidity regulates PTH secretion and reveal an interaction between calcium and pH signaling in this process. This work provides a robust ex vivo model for studying PTG physiology and offers new insight into how metabolic acidosis may contribute to secondary hyperparathyroidism in chronic kidney disease, highlighting OGR1 signaling as a potential therapeutic target.