Uncoupling of K+ and Cl− transport across the cell membrane in the process of regulatory volume decrease

It is accepted that K+ and Cl− flows are coupled tightly in regulatory volume decrease (RVD). However, using self referencing microelectrodes, we proved that K+ and Cl− transport mainly by channels in RVD was uncoupled in nasopharyngeal carcinoma CNE-2Z cells, with the transient K+ efflux activated earlier and sustained Cl− efflux activated later. Hypotonic challenges decreased intracellular pH (pHi), and activated a proton pump-dependent H+ efflux, resulting in a decline of extracellular pH (pHo). Modest decreases of pHo inhibited the volume-activated K+ outflow and RVD, but not the Cl− outflow, while inhibition of H+ efflux or increase of pHo buffer ability promoted K+ efflux and RVD. The results suggest that the temporal dynamics of K+ channel activities is different from that of Cl− channels in RVD, due to differential sensitivity of K+ and Cl− channels to pHo. H+ efflux may play important roles in cell volume regulation, and may be a therapeutic target for human nasopharyngeal carcinoma.