Long-QT mutations in KCNE1 modulate the 17β-estradiol response of Kv7.1/KCNE1.

Erlandsdotter, Lisa-Marie; Giammarino, Lucilla; Halili, Azemine; Nikesjö, Johan; Gréen, Henrik; Odening, Katja E; Liin, Sara I (2023). Long-QT mutations in KCNE1 modulate the 17β-estradiol response of Kv7.1/KCNE1. Science Advances, 9(11), eade7109. American Association for the Advancement of Science 10.1126/sciadv.ade7109

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Estradiol (17[Formula: see text]-E2) is implicated in higher arrhythmia risk of women with congenital or acquired long-QT syndrome (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 17[Formula: see text]-E2 inhibits the human cardiac Kv7.1/KCNE1 channel expressed in Xenopus oocytes. We find that the 17[Formula: see text]-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 17[Formula: see text]-E2, from a wild-type like response to impaired or abolished response. Together, this study increases our understanding of the mechanistic basis for 17[Formula: see text]-E2 inhibition of Kv7.1/KCNE1 and demonstrates mutation-dependent responses to 17[Formula: see text]-E2. These findings suggest that the 17[Formula: see text]-E2 effect on Kv7.1/KCNE1 might contribute to the higher arrhythmia risk of women, particularly in carriers with specific LQTS-associated mutations.

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