Rapidly activating Kv4 voltage-gated ion channels are found in heart, brain, and diverse other tissues including colon and uterus. Kv4.3 can co-assemble with KChIP ancillary subunits, which modify kinetic behavior. We examined the affinity and use dependence of nifedipine block on Kv4.3 and its modulation by KChIP2b. Nifedipine (150 mu M) reduced peak Kv4.3 current similar to 50%, but Kv4.3/KChIP2b current only similar to 27%. Nifedipine produced a very rapid component of open channel block in both Kv4.3 and Kv4.3/KChIP2b. However, recovery from the blocked/inactivated state was strongly sensitive to KChIP2b. Kv4.3 T-half,T-recovery was slowed significantly by nifedipine (120.0 +/-12.4 ms vs. 213.1 +/- 18.2 ms), whereas KChIP2b eliminated nifedipine's effect on recovery: Kv4.3/KChIP2b T-half,T-recovery was 45.3 +/- 7.2 ms (control) and 47.8 +/- 8.2 ms (nifedipine). Consequently, Kv4,3 exhibited use-dependent nifedipine block in response to a series of depolarizing pulses which was abolished by KChIP2b. KChIPs alter drug affinity and use dependence of Kv4.3. (c) 2005 Elsevier Inc. All rights reserved.