Long-QT mutations in KCNE1 modulate the 1713-estradiol response of Kv7.1/KCNE1

Estradiol (1713-E2) is implicated in higher arrhythmia risk of women with congenital or acquired long-QT syn-drome (LQTS) compared to men. However, the underlying mechanisms remain poorly understood, and little is known about the impact of LQTS-associated mutations. We show that 1713-E2 inhibits the human cardiac Kv7.1/ KCNE1 channel expressed in Xenopus oocytes. We find that the 1713-E2 effect depends on the Kv7.1 to KCNE1 stoichiometry, and we reveal a critical function of the KCNE1 carboxyl terminus for the effect. LQTS-associated mutations in the KCNE1 carboxyl terminus show a range of responses to 1713-E2, from a wild-type like response to impaired or abolished response. Together, this study increases our understanding of the mechanistic basis for 1713-E2 inhibition of Kv7.1/KCNE1 and demonstrates mutation-dependent responses to 1713-E2. These findings suggest that the 1713-E2 effect on Kv7.1/KCNE1 might contribute to the higher arrhythmia risk of women, par-ticularly in carriers with specific LQTS-associated mutations.