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‐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. British Journal of Pharmacology (1997) 122 , 187–189; doi: 10.1038/sj.bjp.0701434