Differentiation impairs low pH-induced Ca2+ signaling and ERK phosphorylation in granule precursor tumour cells.
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.
Huang
Wan-Chen
WC
Department of Physiology, Anatomy and Genetics, Sherrington Building, Oxford University, Oxford, United Kingdom.
Swietach
Pawel
P
Vaughan-Jones
Richard D
RD
Glitsch
Maike D
MD
D000143:Acids / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D050052:TRPC Cation Channels / Q000378:metabolism
D000143:Acids; D043562:Receptors, G-Protein-Coupled; D050052:TRPC Cation Channels; D016222:Fibroblast Growth Factor 2; D015544:Inositol 1,4,5-Trisphosphate; D048049:Extracellular Signal-Regulated MAP Kinases