Synergistic Inhibition of the Maximum Conductance of Kv1.5 Channels by Extracellular K + Reduction and Acidification David Fedida, 1, * Shetuan Zhang, 2 Daniel C. H. Kwan, 1 Cyrus Eduljee, 1 and Steven J. Kehl 1 1 Department of Physiology, University of British Columbia, 2146 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3, and 2 Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, University of Manitoba, 351 Tache Avenue, Winnipeg, Manitoba R2H 2A6, Canada Abstract Voltage-gated potassium (Kv) channels exist in the membranes of all living cells. Of the func- tional 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 regu- lated 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 + concentra- tion. 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 K + o -depen- dent, 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 inacti- vated 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 physio- logical H + and K + concentrations represents an important pathway to control Kv channel function in health and disease. Index Entries: Voltage-gated K + channels; inactivation; protons; extracellular potassium con- centration. ORIGINAL ARTICLE © Copyright 2005 by Humana Press Inc. All rights of any nature whatsoever reserved. 1085-9195/05/43:231–242/$30.00 Cell Biochemistry and Biophysics 231 Volume 43, 2005 *Author to whom all correspondence and reprint requests should be addressed. E-mail: fedida@interchange.ubc.ca