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

Abstract 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 (pH i ), and activated a proton pump-dependent H + efflux, resulting in a decline of extracellular pH (pH o ). Modest decreases of pH o inhibited the volume-activated K + outflow and RVD, but not the Cl − outflow, while inhibition of H + efflux or increase of pH o 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 pH o . H + efflux may play important roles in cell volume regulation, and may be a therapeutic target for human nasopharyngeal carcinoma.