The external K+ concentration and mutations in the outer pore mouth affect the inhibition of kv1.5 current by Ni2+.
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 approximately 0.07 mM) > or = Ni2+) (KD approximately 0.15 mM) > Co2+ (KD approximately 1.4 mM) > Mn2+ (KD > 10 mM).
Kwan
Daniel C H
DC
Department of Physiology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
Eduljee
Cyrus
C
Lee
Logan
L
Zhang
Shetuan
S
Fedida
David
D
Kehl
Steven J
SJ
D000818:Animals; D002412:Cations / Q000378:metabolism; D002478:Cells, Cultured; D003001:Cloning, Molecular; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D051666:Kv1.5 Potassium Channel; D051379:Mice; D009532:Nickel / Q000494:pharmacology*; D017354:Point Mutation / Q000235:genetics*; D011188:Potassium / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*
D002412:Cations; C496981:KCNA5 protein, human; C496982:Kcna5 protein, mouse; D051666:Kv1.5 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D009532:Nickel; D011188:Potassium