November 27, 2019eLifeOpen Access

Helix breaking transition in the S4 of HCN channel is critical for hyperpolarization-dependent gating

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Why the study?

HCN channels open on hyperpolarization, but the mechanisms determining gating polarity remain poorly understood.

Population

HCN1 and bipolar channels

Comparison

Replacement of breakpoint serine with a bulky hydrophobic amino acid vs proto-HCN background

Design

All-atom molecular dynamics simulations and functional studies

Authors

Discussion

Informs HCN engineering in arrhythmia models; leaves open clinical translation to human pacemaking.

Population

HCN1 channel (all-atom molecular dynamics simulations) and bipolar channels (functional studies)

Intervention

Hyperpolarization and mutation (replacement of breakpoint serine with a bulky hydrophobic amino acid)

Comparator

Proto-HCN background without mutation

Outcome

Gating polarity and structural changes (S4 helix breaking)surrogate

Reveals an unexpected mechanism of inward rectification involving a linker sub-helix emerging from HCN S4 during hyperpolarization.

Kasimova et al. (2019) studied this question.

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