Differential effects of Kv11.1 activators on Kv11.1a, Kv11.1b and Kv11.1a/Kv11.1b channels

TY - JOUR

T1 - Differential effects of Kv11.1 activators on Kv11.1a, Kv11.1b and Kv11.1a/Kv11.1b channels

AU - Larsen, A P

AU - Bentzen, Bo Hjorth

AU - Grunnet, M

PY - 2010/10

Y1 - 2010/10

N2 - BACKGROUND AND PURPOSE K v11.1 channels are involved in regulating cellular excitability in various tissues including brain, heart and smooth muscle. In these tissues, at least two isoforms, K v11.1a and K v11.1b, with different kinetics, are expressed. K v11.1 activators are potential therapeutic agents, but their effects have only been tested on the K v11.1a isoform. In this study, the effects of two different K v11.1 activators, NS1643 and RPR260243, were characterized on K v11.1a and K v11.1b channels. EXPERIMENTAL APPROACH K v11.1a and K v11.1b 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 v11.1a 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 v11.1a. 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 v11.1b than on K v11.1a. Effects of both compounds on heteromeric K v11.1a/K v11.1b channels were similar to those on K v11.1a. CONCLUSIONS AND IMPLICATIONS Both NS1643 and RPR260243 displayed differential effects on K v11.1a and K v11.1b channels, the effects being relatively more pronounced on K v11.1b channels. This affirms the importance of testing the effect of K v11.1 activators on different channel isoforms.

AB - BACKGROUND AND PURPOSE K v11.1 channels are involved in regulating cellular excitability in various tissues including brain, heart and smooth muscle. In these tissues, at least two isoforms, K v11.1a and K v11.1b, with different kinetics, are expressed. K v11.1 activators are potential therapeutic agents, but their effects have only been tested on the K v11.1a isoform. In this study, the effects of two different K v11.1 activators, NS1643 and RPR260243, were characterized on K v11.1a and K v11.1b channels. EXPERIMENTAL APPROACH K v11.1a and K v11.1b 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 v11.1a 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 v11.1a. 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 v11.1b than on K v11.1a. Effects of both compounds on heteromeric K v11.1a/K v11.1b channels were similar to those on K v11.1a. CONCLUSIONS AND IMPLICATIONS Both NS1643 and RPR260243 displayed differential effects on K v11.1a and K v11.1b channels, the effects being relatively more pronounced on K v11.1b channels. This affirms the importance of testing the effect of K v11.1 activators on different channel isoforms.

KW - Animals

KW - Cresols

KW - Ether-A-Go-Go Potassium Channels

KW - Membrane Potentials

KW - Oocytes

KW - Patch-Clamp Techniques

KW - Phenylurea Compounds

KW - Piperidines

KW - Protein Isoforms

KW - Quinolines

KW - Transfection

KW - Xenopus laevis

U2 - 10.1111/j.1476-5381.2010.00897.x

DO - 10.1111/j.1476-5381.2010.00897.x

M3 - Journal article

C2 - 20880400

SN - 0007-1188

VL - 161

SP - 614

EP - 628

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 3

ER -