The Specific Slow Afterhyperpolarization Inhibitor UCL2077 Is a Subtype-Selective Blocker of the Epilepsy Associated KCNQ Channels

Mutations in members of the KCNQ channel family underlie multiple diseases affecting the nervous and cardiovascular systems. Despite their clinical relevance, research into these channels is limited by the lack of subtype-selective inhibitors, making it difficult to differentiate the physiological function of each family member in vivo. We have proposed that KCNQ channels might partially underlie the calcium-activated slow afterhyper-polarization (sAHP), a neuronal conductance whose molecular components are uncertain. Here, we investigated whether 3-(triphenylmethylaminomethyl) pyridine (UCL2077), identified previously as an inhibitor of the sAHP in neurons, acts on members of the KCNQ family expressed in heterologous cells. We found that 3 mu M UCL2077 strongly inhibits KCNQ1 and KCNQ2 channels and weakly blocks KCNQ4 channels in a voltage-independent manner. In contrast, UCL2077 potentiates KCNQ5 channels at more positive membrane potentials, with little effect at negative membrane potentials. We found that the effect of UCL2077 on KCNQ3 is bimodal: currents are enhanced at negative membrane potentials and inhibited at positive potentials. We found that UCL2077 facilitates KCNQ3 currents by inducing a leftward shift in the KCNQ3 voltage-dependence, a shift dependent on tryptophan 265. Finally, we show that UCL2077 has intermediate effects on KCNQ2/3 heteromeric channels compared with KCNQ2 and KCNQ3 homomers. Together, our data demonstrate that UCL2077 acts on KCNQ channels in a subtype-selective manner. This feature should make UCL2077 a useful tool for distinguishing KCNQ1 and KCNQ2 from less-sensitive KCNQ family members in neurons and cardiac cells in future studies.