Coexpression of IsK and KvLQT1 subunits resulted in a 6-100 fold higher affinity for IKs blockers and dramatically enhanced steady-state currents with activators compared to KvLQT1 alone.
The IsK protein is crucial for modulating the pharmacological sensitivity of IKs channels to both blockers and activators, which has implications for drug specificity in cardiac tissue.
Effect estimate: 6-100 fold higher affinity
IKs channels are composed of IsK and KvLQT1 subunits and underly the slowly activating, voltage-dependent IKs conductance in heart. Although it appears clear that the IsK protein affects both the biophysical properties and regulation of IKs channels, its role in channel pharmacology is unclear. In the present study we demonstrate that KvLQT1 homopolymeric K+ channels are inhibited by the IKs blockers 293B, azimilide and 17-beta-oestradiol. However, IKs channels induced by the coexpression of IsK and KvLQT1 subunits have a 6-100 fold higher affinity for these blockers. Moreover, the IKs activators mefenamic acid and DIDS had little effect on KvLQT1 homopolymeric channels, although they dramatically enhanced steady-state currents through heteropolymeric IKs channels by arresting them in an open state. In summary, the IsK protein modulates the effects of both blockers and activators of IKs channels. This finding is important for the action and specificity of these drugs as IsK protein expression in heart and other tissues is regulated during development and by hormones.
Büsch et al. (Mon,) conducted a other in IKs channel pharmacology. IKs blockers (293B, azimilide, 17-beta-oestradiol) and activators (mefenamic acid, DIDS) vs. KvLQT1 homopolymeric channels was evaluated on Channel affinity and response to blockers and activators (6-100 fold higher affinity). Coexpression of IsK and KvLQT1 subunits resulted in a 6-100 fold higher affinity for IKs blockers and dramatically enhanced steady-state currents with activators compared to KvLQT1 alone.