Key result
Helical HCN-domain acts as a sliding crank to couple voltage- and cAMP-dependent gating in HCN channels.
Why the study?
The structural mechanism coupling cAMP binding to voltage gating in HCN channels was unknown despite available high resolution structures.
Identifies the structural mechanism by which the HCN domain couples cAMP binding to voltage gating in pacemaker channels.
Reveals HCN gating mechanism; hypothesis-generating in animal models, leaves open human therapeutic translation.
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 voltage-dependent gating in three HCN isoforms.
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A 2019 study studied this question. The helical HCN-domain mechanically couples the cyclic nucleotide-binding domain and voltage sensing domain, acting as a sliding crank to convert planar rotational movement into upward displacement.
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