Long-QT mutations in KCNE1 modulate the 17β-estradiol response of Kv7.1/KCNE1
Lisa-Marie Erlandsdotter, Lucilla Giammarino, Azemine Halili, Johan Larsson, Henrik Gréen, Katja E. Odening, Sara I. Liin
Abstract
Estradiol (17 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mo>$</mml:mo> <mml:mi>β</mml:mi> <mml:mo>$</mml:mo> </mml:math> -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 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mo>$</mml:mo> <mml:mi>β</mml:mi> <mml:mo>$</mml:mo> </mml:math> -E2 inhibits the human cardiac Kv7.1/KCNE1 channel expressed in Xenopus oocytes. We find that the 17 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mo>$</mml:mo> <mml:mi>β</mml:mi> <mml:mo>$</mml:mo> </mml:math> -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 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mo>$</mml:mo> <mml:mi>β</mml:mi> <mml:mo>$</mml:mo> </mml:math> -E2, from a wild-type like response to impaired or abolished response. Together, this study increases our understanding of the mechanistic basis for 17 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mo>$</mml:mo> <mml:mi>β</mml:mi> <mml:mo>$</mml:mo> </mml:math> -E2 inhibition of Kv7.1/KCNE1 and demonstrates mutation-dependent responses to 17 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mo>$</mml:mo> <mml:mi>β</mml:mi> <mml:mo>$</mml:mo> </mml:math> -E2. These findings suggest that the 17 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mo>$</mml:mo> <mml:mi>β</mml:mi> <mml:mo>$</mml:mo> </mml:math> -E2 effect on Kv7.1/KCNE1 might contribute to the higher arrhythmia risk of women, particularly in carriers with specific LQTS-associated mutations.