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

Nifedipine can block K+ currents through Kv1.5 channels in an open-channel manner (32). Replacement of internal and external K+ with equimolar Rb+ or Cs+ reduced the potency of nifedipine block of Kv1.5 from an IC50 of 7.3 mu M (K+) to 16.0 muM (Rb+) and 26.9 muM (Cs+). The voltage dependence of bloc k was unaffected, and a single binding site block model was used to describ e block for all three ions. By varying ion species at the intra- and extrac ellular mouth of the channel and by using a nonconducting W472F-Kv1.5 mutan t, we demonstrated that block was conditioned by the ion permeating the por e and, to a lesser extent, by the extracellular ion species alone. In Kv1.5 , the outer pore mutations R487V and R487Y 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 n ormalized reduction and time course of currents blocked by nifedipine in 5, 135, and 300 mM extracellular K+ concentration 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 consisten t with the conclusion that nifedipine block and C-type inactivation in the Kv1.5 channel can coexist but are mediated by distinct mechanisms coordinat ed by outer pore conformation.