We report on the role of K+ currents in the mechanisms regulating the proliferation of UMR 106-01 osteoblastic osteosarcoma cells. Electrophysiological analysis showed that UMR 106-01 cells produce robust K+ currents that can be pharmacologically separated into two major components: a E-4031-susceptible current, I E-4031, and a tetraethylammonium (TEA)-susceptible component, I TEA. Western blot and RT-PCR analysis showed that I E-4031 is produced by ether a go-go (eag)-related channels (ERG). Incubation of the cells with E-4031 enhanced their proliferation by 80%. Application of E-4031 in the bath solution did not induce instantaneous changes in the membrane resting potential or in the level of cytosolic calcium; however, the cells were slightly depolarized and the calcium content was significantly increased upon prolonged incubation with the compound. Taken together these findings indicate that ERG channels can impair cell proliferation. This is a novel finding that underscores new modes of regulation of mitosis by voltage-gated K+ channels and provides an unexpected insight into the current view of the mechanisms governing bone tissue proliferation.