BACKGROUND AND PURPOSE Kv11.1 channels are involved in regulating cellular excitability in various tissues including brain, heart and smooth muscle. In these tissues, at least two isoforms, Kv11.1a and Kv11.1b, with different kinetics, are expressed. Kv11.1 activators are potential therapeutic agents, but their effects have only been tested on the Kv11.1a isoform. In this study, the effects of two different Kv11.1 activators, NS1643 and RPR260243, were characterized on Kv11.1a and Kv11.1b channels.
EXPERIMENTAL APPROACH Kv11.1a and Kv11.1b channels were expressed in Xenopus laevis oocytes, and currents were measured using two-electrode voltage clamp. I/V curves and channel kinetics were measured before and after application of 30 µM NS1643 or 10 µM RPR260243.
KEY RESULTS NS1643 increased steady-state currents through Kv11.1b several fold more than through Kv11.1a channels, without affecting EC50 values. NS1643 increased activation rates and decreased rates of inactivation, recovery from inactivation and deactivation for both channels. Except for activation, where effect of NS1643 was comparable, relative changes were greater for Kv11.1b than for Kv11.1a. RPR260243 increased steady-state currents only through Kv11.1a channels, but slowed the process of deactivation for both channels primarily by decreasing time constant of slow deactivation. This effect was greater on Kv11.1b than on Kv11.1a. Effects of both compounds on heteromeric Kv11.1a/Kv11.1b channels were similar to those on Kv11.1a.
CONCLUSIONS AND IMPLICATIONS Both NS1643 and RPR260243 displayed differential effects on Kv11.1a and Kv11.1b channels, the effects being relatively more pronounced on Kv11.1b channels. This affirms the importance of testing the effect of Kv11.1 activators on different channel isoforms.