@article{30bcef71afc9430384aaa327e2ecca8d,
title = "Bipolar switching by HCN voltage sensor underlies hyperpolarization activation",
abstract = "Despite sharing a common architecture with archetypal voltage-gated ion channels (VGICs), hyperpolarization- and cAMP-activated ion (HCN) channels open upon hyperpolarization rather than depolarization. The basic motions of the voltage sensor and pore gates are conserved, implying that these domains are inversely coupled in HCN channels. Using structure-guided protein engineering, we systematically assembled an array of mosaic channels that display the full complement of voltage-activation phenotypes observed in the VGIC superfamily. Our studies reveal that the voltage sensor of the HCN channel has an intrinsic ability to drive pore opening in either direction and that the extra length of the HCN S4 is not the primary determinant for hyperpolarization activation. Tight interactions at the HCN voltage sensor–pore interface drive the channel into an hERG-like inactivated state, thereby obscuring its opening upon depolarization. This structural element in synergy with the HCN cyclic nucleotide-binding domain and specific interactions near the pore gate biases the channel toward hyperpolarization-dependent opening. Our findings reveal an unexpected common principle underpinning voltage gating in the VGIC superfamily and identify the essential determinants of gating polarity.",
keywords = "Depolarization, EAG, HCN, Hyperpolarization, Ion channel",
author = "John Cowgill and Klenchin, {Vadim A.} and Claudia Alvarez-Baron and Debanjan Tewari and Alexander Blair and Baron Chanda",
note = "Funding Information: We thank G. A. Robertson for providing hEAG1, C. Czajkowski for the pUNIV vector, B. Santoro and S. A. Siegelbaum for mHCN1, M. C. Sanguinetti for mHCN2, and U. B. Kaupp for spHCN. We also thank N. Nallappan for help generating chimeras; N. Nallappan, W. Stevens-Sostre, and T. Tsao for performing frog surgeries and providing oocytes; and M. B. Jackson, L. Delemotte, and G. A. Robertson for their helpful comments and discussions. We thank M. Kasimova and L. Delemotte for sharing unpublished results of their molecular dynamics simulations. This work was supported by funding from the National Institutes of Health to B.C. (Grant NS101723), J.C. (Award T32 HL-07936-17), and C.A.-B. (Award T32 HL-07936-15), American Heart Association to C.A.-B. (Award 17POST33411069), Romnes faculty fellowship (to B.C.), and Hilldale fellowships (to A.B.). Funding Information: T32 HL-07936-17), and C.A.-B. (Award T32 HL-07936-15), American Heart Association to C.A.-B. (Award 17POST33411069), Romnes faculty fellowship (to B.C.), and Hilldale fellowships (to A.B.). Funding Information: We thank M. Kasimova and L. Delemotte for sharing unpublished results of their molecular dynamics simulations. This work was supported by funding from the National Institutes of Health to B.C. (Grant NS101723), J.C. (Award Publisher Copyright: {\textcopyright} 2018 National Academy of Sciences. All rights reserved.",
year = "2019",
month = jan,
day = "8",
doi = "10.1073/pnas.1816724116",
language = "English",
volume = "116",
pages = "670--678",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "2",
}