The external K+ concentration and mutations in the outer pore mouth affect the inhibition of kv1.5 current by Ni2+ |
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Authors: | Kwan Daniel C H Eduljee Cyrus Lee Logan Zhang Shetuan Fedida David Kehl Steven J |
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Institution: | Department of Physiology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3 |
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Abstract: | 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 Ho+, Ni2+ binding to H463 facilitates an outer pore inactivation process that is antagonized by Ko+ and that requires R487. However, whereas Ho+ 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 Ko+ is Zn2+ (KD ~ 0.07 mM) ≥ Ni2+ (KD ~ 0.15 mM) > Co2+ (KD ~ 1.4 mM) > Mn2+ (KD > 10 mM). |
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