PMID: 9524137May 2, 1998Paper

On the mechanism by which 4-Aminopyridine occludes quinidine block of the cardiac K+ channel, hKv1.5

The Journal of General Physiology
F S Chen, David Fedida

Abstract

4-Aminopyridine (4-AP) binds to potassium channels at a site or sites in the inner mouth of the pore and is thought to prevent channel opening. The return of hKv1.5 off-gating charge upon repolarization is accelerated by 4-AP and it has been suggested that 4-AP blocks slow conformational rearrangements during late closed states that are necessary for channel opening. On the other hand, quinidine, an open channel blocker, slows the return or immobilizes off-gating charge only at opening potentials (>-25 mV). The aim of this study was to use quinidine as a probe of open channels to test the kinetic state of 4-AP-blocked channels. In the presence of 0.2-1 mM 4-AP, quinidine slowed charge return and caused partial charge immobilization, corresponding to an increase in the Kd of approximately 20-fold. Peak off-gating currents were reduced and decay was slowed approximately 2- to 2.5-fold at potentials negative to the threshold of channel activation and during depolarizations shorter than normally required for channel activation. This demonstrated access of quinidine to 4-AP-blocked channels, a lack of competition between the two drugs, and implied allosteric modulation of the quinidine binding site by 4-AP resident within the channe...Continue Reading

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Citations

Apr 3, 1999·British Journal of Pharmacology·C ParkerD Fedida
Oct 15, 2009·Journal of Medical Engineering & Technology·Hao DingYanjun Zeng
Feb 5, 2008·American Journal of Physiology. Heart and Circulatory Physiology·Joëlle Abi-CharStéphane N Hatem
Jan 16, 2003·The Journal of Physiology·Shimin WangRandall L Rasmusson
Nov 24, 1999·The American Journal of Physiology·J C Hesketh, D Fedida

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