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Insights into the molecular mechanism for hyperpolarization-dependent activation of HCN channels.

08:00 EDT 3rd August 2018 | BioPortfolio

Summary of "Insights into the molecular mechanism for hyperpolarization-dependent activation of HCN channels."

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels are both voltage- and ligand-activated membrane proteins that contribute to electrical excitability and pace-making activity in cardiac and neuronal cells. These channels are members of the voltage-gated Kv channel superfamily and cyclic nucleotide-binding domain subfamily of ion channels. HCN channels have a unique feature that distinguishes them from other voltage-gated channels: the HCN channel pore opens in response to hyperpolarizing voltages instead of depolarizing voltages. In the canonical model of electromechanical coupling, based on Kv channels, a change in membrane voltage activates the voltage-sensing domains (VSD) and the activation energy passes to the pore domain (PD) through a covalent linker that connects the VSD to the PD. In this investigation, the covalent linkage between the VSD and PD, the S4-S5 linker, and nearby regions of spHCN channels were mutated to determine the functional role each plays in hyperpolarization-dependent activation. The results show that: () the S4-S5 linker is not required for hyperpolarization-dependent activation or ligand-dependent gating; () the S4 C-terminal region (S4) is not necessary for ligand-dependent gating but is required for hyperpolarization-dependent activation and acts like an autoinhibitory domain on the PD; () the S5 region is involved in VSD-PD coupling and holding the pore closed; and () spHCN channels have two voltage-dependent processes, a hyperpolarization-dependent activation and a depolarization-dependent recovery from inactivation. These results are inconsistent with the canonical model of VSD-PD coupling in Kv channels and elucidate the mechanism for hyperpolarization-dependent activation of HCN channels.

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This article was published in the following journal.

Name: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
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