Abstract
In contrast to most voltage-gated ion channels, hyperpolarization- and cAMP gated (HCN) ion channels open on hyperpolarization. Structure-function studies show that the voltage-sensor of HCN channels are unique but the mechanisms that determine gating polarity remain poorly understood. All-atom molecular dynamics simulations (~20 μs) of HCN1 channel under hyperpolarization reveals an initial downward movement of the S4 voltage-sensor but following the transfer of last gating charge, the S4 breaks into two sub-helices with the lower sub-helix becoming parallel to the membrane. Functional studies on bipolar channels show that the gating polarity strongly correlates with helical turn propensity of the substituents at the breakpoint. Remarkably, in a proto-HCN background, the replacement of breakpoint serine with a bulky hydrophobic amino acid is sufficient to completely flip the gating polarity from inward to outward-rectifying. Our studies reveal an unexpected mechanism of inward rectification involving a linker sub-helix emerging from HCN S4 during hyperpolarization.
Highlights
The hyperpolarization-activated and cyclic nucleotide activated ion channels are found in the pacemaking cells of heart and brain where they play a singular role in regulating rhythmic electrical oscillations (Brown et al, 1979; Ludwig et al, 1998; Santoro et al, 1998)
We sought to facilitate the movement of gating charges by further hydrating water crevices inside the voltage-sensing domain (VSD)
By comparing the sequences of HCN and ether-a -go-go (EAG) homologs, which activate and gate much faster, we identified two positions in S1 with large hydrophobic residues in HCN channels compared to smaller, less hydrophobic residues in the EAG family (Figure 1—figure supplement 1A,C)
Summary
The hyperpolarization-activated and cyclic nucleotide activated ion channels are found in the pacemaking cells of heart and brain where they play a singular role in regulating rhythmic electrical oscillations (Brown et al, 1979; Ludwig et al, 1998; Santoro et al, 1998). Unlike other members of the voltage-gated ion channel family, these channels open at membrane potentials below the threshold of action potential and depolarize the membrane by increasing the permeability to Na+ ions (Brown et al, 1979). Their slow gating kinetics and low permeability determine the frequency of action potential spikes (Larson et al, 2013; Sharpe et al, 2017). The HCN channels are remarkably similar to other voltage-gated ion channels They are tetrameric and each subunit consists of a voltage-sensing domain (VSD) (S1-S4 helices) and pore-forming domain (S5-S6 helices) (Lee and MacKinnon, 2017). The S4 segment of HCN1 channel is at least two helical
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
