Synergistic inhibition of the maximum conductance of Kv1.5 channels by extracellular K+ reduction and acidification

Voltage-gated potassium (Kv) channels exist in the membranes of all living cells. Of the functional classes of Kv channels, the Kv1 channels are the largest and the best studied and are known to play essential roles in excitable cell function, providing an essential counterpoint to the various inward currents that trigger excitability. The serum potassium concentration [K-o(+)] is tightly regulated in mammals and disturbances can cause significant functional alterations in the electrical behavior of excitable tissues in the nervous system and the heart. At least some of these changes may be mediated by Kv channels that are regulated by changes in the extracellular K+ concentration. As well as changes in serum [K-o(+)], tissue acidification is a frequent pathological condition known to inhibit Shaker and Kv1 voltage-gated potassium channels. In recent studies, it has become recognized that the acidification-induced inhibition of some Kv1 channels is K10-dependent, and the suggestion has been made that pH and K-o(+) may regulate the channels via a common mechanism. Here we discuss P/C type inactivation as the common pathway by which some Kv channels become unavailable at acid pH and lowered K-o(+). It is suggested that binding of protons to a regulatory site in the outer pore mouth of some Kv channels favors transitions to the inactivated state, whereas K+ ions exert countereffects. We suggest that modulation of the number of excitable voltage-gated K+ channels in the open vs inactivated states of the channels by physiological H+ and K+ concentrations represents an important pathway to control Kv channel function in health and disease.