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

Abstract

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-β-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.