Voltage-gated ion channels, specifically Na, K, and Ca channels, as well as other channel types share several features in common, in particular slow inactivation, a process that is not well understood at the molecular level. Several years ago, this laboratory discovered that K channel inactivation in squid giant axons was voltage-shifted by changes in the intracellular pH, specifically a 10 mV shift in the midpoint of the inactiavtion curve on the voltage axis per unit pH change in the 6 < pH < 10 range. A similar result has not been reported for the Shaker K channel expressed heterologously in Xenopus oocytes. Preliminary results have suggested the absence of this effect, even though slow inactivation of the Shaker K channel is remarkably similar to that of the squid K channel. A comparative analysis of the pH effect using site-directed mutagenesis of both channels, each heterologously expressed, should yield significant insight into the slow inactivation mechanism.