The fully activated open state of KCNQ1 controls the cardiac “fight-or-flight” response

The cardiac KCNQ1 + KCNE1 (I_Ks) channel regulates heart rhythm under both normal and stress conditions. Under stress, the β-adrenergic stimulation elevates the intracellular cyclic adenosine monophosphate (cAMP) level, leading to KCNQ1 phosphorylation by protein kinase A and increased I_Ks, which shortens action potentials to adapt to accelerated heart rate. An impaired response to the β-adrenergic stimulation due to KCNQ1 mutations is associated with the occurrence of a lethal congenital long QT syndrome (type 1, also known as LQT1). However, the underlying mechanism of β-adrenergic stimulation of I_Ks remains unclear, impeding the development of new therapeutics. Here, we find that the unique properties of KCNQ1 channel gating with two distinct open states are key to this mechanism. KCNQ1's fully activated open (AO) state is more sensitive to cAMP than its intermediate open state. By enhancing the AO state occupancy, the small molecules ML277 and C28 are found to effectively enhance the cAMP sensitivity of the KCNQ1 channel, independent of KCNE1 association. This finding of enhancing AO state occupancy leads to a potential novel strategy to rescue the response of I_Ks to β-adrenergic stimulation in LQT1 mutants. The success of this approach is demonstrated in cardiac myocytes and also in a high-risk LQT1 mutation. In conclusion, the present study not only uncovers the key role of the AO state in I_Ks channel phosphorylation, but also provides a target for antiarrhythmic strategy.