Potassium channel inhibition reduces cell proliferation in the GH3 pituitary cell line

Potassium (K+) conductances are known to be involved in cell proliferation of a number of nonexcitable cell types. The nature of the mechanism by which K+ channel inhibition reduces cell proliferation has remained elusive despite intensive search. We investigated whether such a phenomenon could be demonstrated in excitable cells, using the GH3 pituitary cell line as a cell model. Our aims were: 1) to study the effect of K+ channel inhibition on the proliferation of GH3 cells; and 2) to investigate the putative intracellular signals involved in this inhibition. Tetraethylammonium chloride (TEA), a blocker of the calcium (Ca2+)-dependent K+ conductances of GH3, was found to reversibly inhibit cell proliferation, as measured by 3H-thymidine incorporation. Cell cycle block specifically occurred at the G1/S phase of the cell cycle. This inhibition of proliferation was observed for 1-4 mM TEA, which suppressed most of the Ca2+-activated K+ current and part of the inward rectifying K+ current, as shown by electrophysiological experiments. Increasing extracellular K+ concentrations with KCI also inhibited cell proliferation in a dose-dependent manner. Both TEA and KCl depolarized the cells and increased intracellular Ca2+ levels ([Ca2+]i), showing that, in this type of excitable cell, inhibition of cell proliferation can be associated with elevated Ca2+ levels. Ca2+ and membrane resting potential (MRP) were considered as possible messengers of this inhibition. Our results suggest that cell cycle arrest of GH3 cells by K+ channel block probably involves an additional pathway, distinct from those of Ca2+ and MRP.