Membrane potential modulates ERK activity and cell proliferation in human cells

Plasma membrane potential has been linked to cell proliferation for over 40 years in vertebrate cells. In this study, we experimentally demonstrated that membrane depolarization promotes mitosis and that this process depends on the voltage-dependent activation of extracellular signal-regulated kinase (ERK) in human cells. Notably, ERK activity showed a clear dependence on the membrane potential, independent of growth factor stimulation. This voltage dependence was observed even near the resting membrane potential, indicating that small shifts in the resting potential can influence proliferative activity. Voltage-dependent ERK activity is derived from the altered dynamics of phosphatidylserine and is not mediated by calcium influx from the extracellular space. These findings suggest that fundamental biological processes such as cell proliferation are regulated by the physicochemical properties of membrane lipids. This study highlights the broader physiological roles of membrane potentials beyond action potentials, which are well-established in neural systems.