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The External K⁺ Concentration and Mutations in the Outer Pore Mouth Affect the Inhibition of Kv1.5 Current by Ni²⁺

Department of Physiology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3

Correspondence: Address reprint requests to S. J. Kehl, E-mail: skehl{at}interchange.ubc.ca.

By examining the consequences both of changes of [K⁺]_o and of point mutations in the outer pore mouth, our goal was to determine if the mechanism of the block of Kv1.5 ionic currents by external Ni²⁺ is similar to that for proton block. Ni²⁺ block is inhibited by increasing [K⁺]_o, by mutating a histidine residue in the pore turret (H463Q) or by mutating a residue near the pore mouth (R487V) that is the homolog of Shaker T449. Aside from a slight rightward shift of the Q-V curve, Ni²⁺ had no effect on gating currents. We propose that, as with H_o⁺, Ni²⁺ binding to H463 facilitates an outer pore inactivation process that is antagonized by K_o⁺ and that requires R487. However, whereas H_o⁺ substantially accelerates inactivation of residual currents, Ni²⁺ is much less potent, indicating incomplete overlap of the profiles of these two metal ions. Analyses with Co²⁺ and Mn²⁺, together with previous results, indicate that for the first-row transition metals the rank order for the inhibition of Kv1.5 in 0 mM K_o⁺ is Zn²⁺ (K_D 0.07 mM) Ni²⁺ (K_D 0.15 mM) > Co²⁺ (K_D 1.4 mM) > Mn²⁺ (K_D > 10 mM).

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