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Differential effects of K v 11.1 activators on K v 11.1a, K v 11.1b and K v 11.1a/K v 11.1b channels
Author(s) -
Larsen AP,
Bentzen BH,
Grunnet M
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.00897.x
Subject(s) - kinetics , chemistry , xenopus , biophysics , steady state (chemistry) , patch clamp , potassium channel , stereochemistry , biochemistry , biology , physics , receptor , quantum mechanics , gene
BACKGROUND AND PURPOSE K v 11.1 channels are involved in regulating cellular excitability in various tissues including brain, heart and smooth muscle. In these tissues, at least two isoforms, K v 11.1a and K v 11.1b, with different kinetics, are expressed. K v 11.1 activators are potential therapeutic agents, but their effects have only been tested on the K v 11.1a isoform. In this study, the effects of two different K v 11.1 activators, NS1643 and RPR260243, were characterized on K v 11.1a and K v 11.1b channels. EXPERIMENTAL APPROACH K v 11.1a and K v 11.1b 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 K v 11.1a channels, without affecting EC 50 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 K v 11.1a. 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 K v 11.1b than on K v 11.1a. Effects of both compounds on heteromeric K v 11.1a/K v 11.1b channels were similar to those on K v 11.1a. CONCLUSIONS AND IMPLICATIONS Both NS1643 and RPR260243 displayed differential effects on K v 11.1a and K v 11.1b channels, the effects being relatively more pronounced on K v 11.1b channels. This affirms the importance of testing the effect of K v 11.1 activators on different channel isoforms.