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The HCN domain couples voltage gating and cAMP response in hyperpolarization-activated cyclic nucleotide-gated channels

Saponaro, Andrea ; Gasparri, Federica ; Bauer, Daniel ; Gross, Christine ; Pisoni, Matteo ; Abbandonato, Gerardo ; Hamacher, Kay ; Santoro, Bina ; Moroni, Anna ; Porro, Alessandro ; Thiel, Gerhard (2022):
The HCN domain couples voltage gating and cAMP response in hyperpolarization-activated cyclic nucleotide-gated channels. (Publisher's Version)
In: eLife, (8), eLife Sciences Publications, e-ISSN 2050-084X,
DOI: 10.26083/tuprints-00013356,
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Item Type: Article
Origin: Secondary publication
Status: Publisher's Version
Title: The HCN domain couples voltage gating and cAMP response in hyperpolarization-activated cyclic nucleotide-gated channels
Language: English
Abstract:

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control spontaneous electrical activity in heart and brain. Binding of cAMP to the cyclic nucleotide-binding domain (CNBD) facilitates channel opening by relieving a tonic inhibition exerted by the CNBD. Despite high resolution structures of the HCN1 channel in the cAMP bound and unbound states, the structural mechanism coupling ligand binding to channel gating is unknown. Here we show that the recently identified helical HCN-domain (HCND) mechanically couples the CNBD and channel voltage sensing domain (VSD), possibly acting as a sliding crank that converts the planar rotational movement of the CNBD into a rotational upward displacement of the VSD. This mode of operation and its impact on channel gating are confirmed by computational and experimental data showing that disruption of critical contacts between the three domains affects cAMP- and voltagedependent gating in three HCN isoforms.

Journal or Publication Title: eLife
Issue Number: 8
Publisher: eLife Sciences Publications
Collation: 23 Seiten
Classification DDC: 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin, Gesundheit
Divisions: 10 Department of Biology > Developmental Biology and Neurogenetics
Date Deposited: 10 Feb 2022 08:36
Last Modified: 10 Feb 2022 08:37
DOI: 10.26083/tuprints-00013356
Corresponding Links:
URN: urn:nbn:de:tuda-tuprints-133568
URI: https://tuprints.ulb.tu-darmstadt.de/id/eprint/13356
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