Molecular basis for differential sensitivity of KCNQ and I-Ks channels to the cognitive enhancer XE991

Channels formed by coassembly of the KCNQ1 (KvLQT1) subunit and the minK su bunit underlie slowly activating cardiac delayed rectifier (I-Ks) in the he art, whereas two other members of the KCNQ channel family, KCNQ2 and KCNQ3, coassemble to underlie the M current in the nervous system. Because of the ir important physiological function, KCNQ channels have potential as drug t argets, and an understanding of possible mechanisms that would enable tissu e-specific targeting of these channels will be of significant value to drug development. In this study, we examined the role of the minK subunit in de termining the response of KCNQ1 channels to blockade by the cognitive enhan cer XE991. Coexpression with minK markedly decreased the sensitivity of KCN Q1 to blockade by XE991. When measured at the end of a 500-ms step, XE991 b lockade of the KCNQ1+minK current had a K-D value of 11.1 +/- 1.8 mu M, app roximately 14-fold less sensitive than the block of the KCNQ1 current (K-D = 0.78 +/- 0.05 mu M). In addition, XE991 reduced activation and deactivati on time constants and caused a rightward shift in the activation curve of K CNQ1+minK, but affected none of these parameters for KCNQ1 alone. Also, XE9 91 block of KCNQ1+minK, but not of KCNQ1, was time- and voltage-dependent. We conclude that the presence of minK in the I-Ks channel complex gives ris e to differential sensitivity of KCNQ and I-Ks channels to blockade by XE99 1. Our results have implications for drug development by demonstrating the important potential role of accessory subunits in determining the pharmacol ogical properties of KCNQ channels.