Structural basis for hyperpolarization-dependent opening of human HCN1 channel.

TitleStructural basis for hyperpolarization-dependent opening of human HCN1 channel.
Publication TypeJournal Article
Year of Publication2024
AuthorsBurtscher V, Mount J, Huang J, Cowgill J, Chang Y, Bickel K, Chen J, Yuan P, Chanda B
JournalNat Commun
Volume15
Issue1
Pagination5216
Date Published2024 Jun 18
ISSN2041-1723
KeywordsCryoelectron Microscopy, Humans, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Ion Channel Gating, Membrane Potentials, Models, Molecular, Potassium Channels
Abstract

Hyperpolarization and cyclic nucleotide (HCN) activated ion channels are critical for the automaticity of action potentials in pacemaking and rhythmic electrical circuits in the human body. Unlike most voltage-gated ion channels, the HCN and related plant ion channels activate upon membrane hyperpolarization. Although functional studies have identified residues in the interface between the voltage-sensing and pore domain as crucial for inverted electromechanical coupling, the structural mechanisms for this unusual voltage-dependence remain unclear. Here, we present cryo-electron microscopy structures of human HCN1 corresponding to Closed, Open, and a putative Intermediate state. Our structures reveal that the downward motion of the gating charges past the charge transfer center is accompanied by concomitant unwinding of the inner end of the S4 and S5 helices, disrupting the tight gating interface observed in the Closed state structure. This helix-coil transition at the intracellular gating interface accompanies a concerted iris-like dilation of the pore helices and underlies the reversed voltage dependence of HCN channels.

DOI10.1038/s41467-024-49599-x
Alternate JournalNat Commun
PubMed ID38890331
PubMed Central IDPMC11189445
Grant ListR35 GM144045 / GM / NIGMS NIH HHS / United States
T32 GM139789 / GM / NIGMS NIH HHS / United States
NS101723 / / U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) /
GM143440 / / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) /
T32 GM108539 / GM / NIGMS NIH HHS / United States
GM144045 / / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) /
GM139789 / / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) /
R01 GM143440 / GM / NIGMS NIH HHS / United States
R01 NS101723 / NS / NINDS NIH HHS / United States