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

• Published in: Science advances Vol. 9; no. 11; p. eade7109
• Main Authors: Erlandsdotter, Lisa-Marie, Giammarino, Lucilla, Halili, Azemine, Nikesjö, Johan, Gréen, Henrik, Odening, Katja E, Liin, Sara I
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 17-03-2023
• Subjects: Biomedicine and Life Sciences; Biophysics; Female; Heart; Heterozygote; Humans; Long QT Syndrome - genetics; Male; Mutation; Potassium Channels, Voltage-Gated - genetics; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.ade7109

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
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.