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Influence of permeating ions on Kv1.5 channel block by nifedipine

University of British Columbia

Nifedipine antagonizes current flow through both cardiovascular L-type Ca2+ channels and voltage-gated K+ (Kv) channels. Work from our lab has shown that nifedipine blocks human heart Kv1.5 current when channels are expressed in HEK cells, and an open channel block mechanism was suggested. Here, the potency of nifedipine block of K+, Rb+, and Cs+ currents was investigated, and found to be different with Kd's of 7.3, 16.0, and 26.9 µM, respectively, when internal and external K+ were replaced with equimolar Rb+ or Cs+ . The voltage-dependence of block was unaffected and block with all three ions conformed to a single binding site block model. Varying ion species at the intracellular and extracellular sides of the channel, and using a non-conducting W472F-Kv1.5 mutant, demonstrated that block was conditioned by the ion permeating the pore, and to a lesser extent by the extracellular ion species alone. In Kv1.5 the outer pore mutant R487V reduced nifedipine potency close to that of Kv4.2, and other Kv channels with an equivalent valine. Although changing this residue can affect C-type inactivation of Kv channels, the normalized reduction and time course of currents blocked by nifedipine in 5, 135, and 300 mM K+0 was the same. Similarly, a mean recovery time constant from nifedipine block of 316 ms was unchanged (332 ms) after 5 s prepulses to allow C-type inactivation. This is consistent with the conclusion that nifedipine block and C-type inactivation in the Kv1.5 channel can coexist, but are mediated by distinct mechanisms coordinated by outer pore conformation. [Scientific formulae used in this abstract could not be reproduced.]

Thesis/Dissertation

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2009-07-28

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http://hdl.handle.net/2429/11375

Physiology

University of British Columbia

UBCV

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