Key result
IRK1 channels strongly select TEA over other QAs due to differing unbinding kinetics, with a 30-fold drop in binding rate when QA methylene groups increase from three to four.
Differences in QA selectivity between IRK1 and ROMK1 channels result primarily from differing unbinding kinetics, suggesting a constricted pathway of approximately 9 A to the QA-binding locus.
Highlights kinetic basis of IRK1 QA selectivity in animals; leaves open relevance to human cardiac channels.
We examined block of two inward-rectifier K+ channels, IRK1 and ROMK1, by a series of intracellular symmetric quaternary alkylammonium ions (QAs) whose side chains contain one to five methylene groups. As shown previously, the ROMK1 channels bind larger QAs with higher affinity. In contrast, the IRK1 channels strongly select TEA over smaller or larger QAs. This remarkable difference in QA selectivity between the two channels results primarily from differing QA unbinding kinetics. The apparent rate constant for binding (kon) of all examined QAs is significantly smaller than expected for a diffusion-limited process. Furthermore, a large ( approximately 30-fold) drop in kon occurs when the number of methylene groups in QAs increases from three to four. These observations argue that between the intracellular solution and the QA-binding locus, there exists a constricted pathway, whose dimension ( approximately 9 A) is comparable to that of a K+ ion with a single H2O shell.
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Guo et al. (2001) studied this question. Quaternary alkylammonium ions (QAs) was evaluated on Kinetics of inward-rectifier K+ channel block (IRK1 and ROMK1). IRK1 channels strongly select TEA over other QAs due to differing unbinding kinetics, with a 30-fold drop in binding rate when QA methylene groups increase from three to four.
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