Purinergic ligands induce extracellular acidification and increased ATP turnover in HepG2 cells.

Nucleosides and nucleotides at μM concentrations stimulated a 300% increase in acid secretion in HepG2 cells, which was quantitatively accounted for as increased export of lactate generated by glycogenolysis. Agonist selectivity encompassed nucleosides and nucleotides for all 5 natural nucleobases and, along with antagonist profiles, was inconsistent with a role for purinergic receptors in mediating this activity. Agonist catabolism did not contribute significantly to either low selectivity or lactate production. Lactate production was driven by an increase in ATP turnover of as much as 56%. For some agonists, especially adenosine, ATP turnover decreased precipitously at mM concentrations, correlating with known adenosine-stimulated apoptosis. We propose that nucleoside/nucleotide agonists induce a futile energy cycle via a novel mechanism, which results in increased ATP turnover and initiates a continuum of events that for some agonists culminates in apoptosis. • Purinergic agonists induce up to 300% increase in acid secretion in HepG2 cells at μM concentrations. • Agonist selectivity is very low and encompasses all natural nucleosides and nucleotides. • Acid secretion is driven by increased ATP turnover by as much as 56% over control levels. • Subsequent precipitous decline in ATP turnover at mM concentrations correlates with apoptosis. [ABSTRACT FROM AUTHOR]