Kv4.2-encoded A-type K⁺ channels play an important role in controlling neuronal excitability and are subject to modulation by various protein kinases including extracellular-signal regulated kinase (ERK). In studies of ERK modulation, the organic compound U0126 is often used to suppress the activity of MEK, which is an immediate upstream kinase of ERK. We have observed that the inactivation time constant of heterologously expressed Kv4.2 channels was accelerated by U0126 at 1-20 µM. This effect, however, was not Kv4 family specific as U0126 also converted non-inactivating K⁺ currents mediated by Kv1.1 subunits into transient ones. To determine whether U0126 exerted these effects through kinase inhibition, we tested U0125, a derivative of U0126 but is less potent in MEK inhibition. At the same concentrations, U0125 showed similar effects as U0126 on channel inactivation. Finally, we expressed a mutant form of Kv4.2 in which three identified ERK phosphorylation sites (T602, T607, and S616) were replaced with alanines. The inactivation of K⁺ currents mediated by this mutant was still accelerated by U0126. Our data favor the conclusion that the increase in the rate of channel inactivation by U0126 is likely to be independent of protein kinase inhibition and instead represents a direct action on channel gating.