Bipolar switching by HCN voltage sensor underlies hyperpolarization activation

John Cowgill, Vadim A. Klenchin, Claudia Alvarez-Baron, Debanjan Tewari, Alexander Blair, Baron Chanda

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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.

Original languageEnglish
Pages (from-to)670-678
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number2
StatePublished - Jan 8 2019


  • Depolarization
  • EAG
  • HCN
  • Hyperpolarization
  • Ion channel


Dive into the research topics of 'Bipolar switching by HCN voltage sensor underlies hyperpolarization activation'. Together they form a unique fingerprint.

Cite this