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. Altho ugh it appears clear that the I-sK protein affects both the biophysica l properties and regulation of I-Ks channels, its role in channel phar macology is unclear. In the present study we demonstrate that KvLQT1 h omopolymeric K+ channels are inhibited by the I-Ks blockers 293B, azim ilide and 17-beta-oestradiol. However, I-Ks channels induced by the co expression of I-sK and KvLQT1 subunits have a 6-100 fold higher affini ty for these blockers. Moreover, the I-Ks activators mefenamic acid an d DIDS had little effect on KvLQT1 homopolymeric channels, although th ey dramatically enhanced steady-state currents through heteropolymeric I-Ks channels by arresting them in an open state. In summary, the I-s K protein modulates the effects of both blockers and activators of I-K s channels. This finding is important for the action and specificity o f these drugs as I-sK protein expression in heart and other tissues is regulated during development and by hormones.