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Gating-Related Molecular Motions in the Extracellular Domain of the IKs Channel: Implications for IKs Channelopathy

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Abstract

Cardiac slow delayed rectifier (IKs) channel complex consists of KCNQ1 channel and KCNE1 auxiliary subunits. The extracellular juxtamembranous region of KCNE1 is an unstructured loop that contacts multiple KCNQ1 positions in a gating-state-dependent manner. Congenital arrhythmia-related mutations have been identified in the extracellular S1–S2 linker of KCNQ1. These mutations manifest abnormal phenotypes only when coexpressed with KCNE1, pointing to the importance of proper KCNQ1/KCNE1 interactions here in IKs channel function. We investigate the interactions between the KCNE1 loop (positions 36–47) and KCNQ1 S1–S2 linker (positions 140–148) by means of disulfide trapping and voltage clamp techniques. During transitions among the resting-state conformations, KCNE1 positions 36–43 make contacts with KCNQ1 positions 144, 145, and 147 in a parallel fashion. During conformational changes in the activated state, KCNE1 position 40 can make contacts with all three KCNQ1 positions, while the neighboring KCNE1 positions (36, 38, 39, and 41) can make contact with KCNQ1 position 147. Furthermore, KCNQ1 positions 143 and 146 are high-impact positions that cannot tolerate cysteine substitution. To maintain the proper IKs channel function, position 143 requires a small side chain with a hydroxyl group, and position 146 requires a negatively charged side chain. These data and the proposed molecular motions provide insights into the mechanisms by which mutations in the extracellular juxtamembranous region of the IKs channel impair its function.

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Acknowledgments

This study was supported by RO1 HL67840 from National Heart, Lung and Blood Institute, and R21 AT0044601 from National Center for Complementary and Alternative Medicine, of National Institutes of Health (to GNT).

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Authors and Affiliations

  1. Department of Physiology and Biophysics, Virginia Commonwealth University, 1101 E. Marshall Street, Sanger 3-042a, Richmond, VA, 23298, USA

    Yu Hong Wang, Min Jiang, Xu Lin Xu, Kai-Ling Hsu, Mei Zhang & Gea-Ny Tseng

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  1. Yu Hong Wang
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  2. Min Jiang
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  3. Xu Lin Xu
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  4. Kai-Ling Hsu
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  6. Gea-Ny Tseng
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Correspondence to Gea-Ny Tseng.

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Wang, Y.H., Jiang, M., Xu, X.L. et al. Gating-Related Molecular Motions in the Extracellular Domain of the IKs Channel: Implications for IKs Channelopathy. J Membrane Biol 239, 137–156 (2011). https://doi.org/10.1007/s00232-010-9333-7

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