Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Extracellular acidification is a hallmark of a number of debilitating pathologies including cancer, ischemia and inflammation. We have recently shown that in human granule precursor tumour cells a fall in extracellular pH triggers increases in intracellular Ca(2+) concentration through activation of G-protein coupled proton-sensing receptors coupling to phospholipase C. This pH-dependent rise in cytosolic Ca(2+) led to activation of the extracellular signal-regulated kinase ERK, providing a mechanistic explanation of how extracellular acidification can promote tumour growth. We now find that differentiation of granule precursor tumour cells profoundly affects their ability to respond to extracellular acidification with gene transcription. Differentiating cells have a lower Ca(2+) release probability from intracellular Ca(2+) stores upon acidification and cells that respond have a significantly smaller and slower Ca(2+) signal than proliferating cells. Importantly, Ca(2+) release in differentiating cells fails to evoke ERK phosphorylation. This altered responsiveness of differentiating cells is not due to reduced proton-sensing receptor expression or diminished Ca(2+) store content. Rather, our results suggest that in differentiating cells, the proton-sensing receptor couples less effectively to phospholipase C activation and IP(3) formation. Hence, the ability of human granule cells to respond to extracellular acidification by generating Ca(2+) signals and ERK activation is state-dependent, being lost upon differentiation.

Original publication




Journal article


Cell Calcium

Publication Date





391 - 399


Acids, Calcium Signaling, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Down-Regulation, Extracellular Signal-Regulated MAP Kinases, Extracellular Space, Fibroblast Growth Factor 2, Humans, Hydrogen-Ion Concentration, Inositol 1,4,5-Trisphosphate, Intracellular Space, Neoplasms, Phosphorylation, Receptors, G-Protein-Coupled, TRPC Cation Channels