The role of the I-sK protein in the specific pharmacological properties of the I-Ks channel complex

I-Ks channels are composed of I-sK and KvLQT1 subunits and underly the slowly activating, voltage-dependent I-Ks conductance in heart. Although it appears clear that the I-sK protein affects both the biophysical properties and regulation of I-Ks channels, its role in channel pharmacology is unclear. In the present study we demonstrate that KvLQT1 homopolymeric K+ channels are inhibited by the I-Ks blockers 293B, azimilide and 17-beta-oestradiol. However, I-Ks channels induced by the coexpression of I-sK and KvLQT1 subunits have a 6-100 fold higher affinity for these blockers. Moreover, the I-Ks activators mefenamic acid and DIDS had little effect on KvLQT1 homopolymeric channels, although they dramatically enhanced steady-state currents through heteropolymeric I-Ks channels by arresting them in an open state. In summary, the I-sK protein modulates the effects of both blockers and activators of I-Ks channels. This finding is important for the action and specificity of these drugs as I-sK protein expression in heart and other tissues is regulated during development and by hormones.