Click
here to close Hello! We notice that
you are using Internet Explorer, which is not supported by Echinobase
and may cause the site to display incorrectly. We suggest using a
current version of Chrome,
FireFox,
or Safari.
Proc Natl Acad Sci U S A
2018 Aug 21;11534:E8086-E8095. doi: 10.1073/pnas.1805596115.
Show Gene links
Show Anatomy links
Insights into the molecular mechanism for hyperpolarization-dependent activation of HCN channels.
Flynn GE
,
Zagotta WN
.
???displayArticle.abstract???
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: (i) the S4-S5 linker is not required for hyperpolarization-dependent activation or ligand-dependent gating; (ii) the S4 C-terminal region (S4C-term) is not necessary for ligand-dependent gating but is required for hyperpolarization-dependent activation and acts like an autoinhibitory domain on the PD; (iii) the S5N-term region is involved in VSD-PD coupling and holding the pore closed; and (iv) 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.
Bell,
Changes in local S4 environment provide a voltage-sensing mechanism for mammalian hyperpolarization-activated HCN channels.
2004, Pubmed
Bell,
Changes in local S4 environment provide a voltage-sensing mechanism for mammalian hyperpolarization-activated HCN channels.
2004,
Pubmed
Biel,
Hyperpolarization-activated cation channels: from genes to function.
2009,
Pubmed
Biel,
Cyclic nucleotide-gated channels.
2009,
Pubmed
Blunck,
Mechanism of electromechanical coupling in voltage-gated potassium channels.
2012,
Pubmed
Craven,
Salt bridges and gating in the COOH-terminal region of HCN2 and CNGA1 channels.
2004,
Pubmed
Craven,
CNG and HCN channels: two peas, one pod.
2006,
Pubmed
DeBerg,
Structure and Energetics of Allosteric Regulation of HCN2 Ion Channels by Cyclic Nucleotides.
2016,
Pubmed
Decher,
Voltage-dependent gating of hyperpolarization-activated, cyclic nucleotide-gated pacemaker channels: molecular coupling between the S4-S5 and C-linkers.
2004,
Pubmed
Fernández-Mariño,
Gating interaction maps reveal a noncanonical electromechanical coupling mode in the Shaker K+ channel.
2018,
Pubmed
Flynn,
Molecular mechanism underlying phosphatidylinositol 4,5-bisphosphate-induced inhibition of SpIH channels.
2011,
Pubmed
,
Echinobase
Flynn,
Structure and rearrangements in the carboxy-terminal region of SpIH channels.
2007,
Pubmed
Gauss,
Molecular identification of a hyperpolarization-activated channel in sea urchin sperm.
1998,
Pubmed
,
Echinobase
Gordon,
A histidine residue associated with the gate of the cyclic nucleotide-activated channels in rod photoreceptors.
1995,
Pubmed
Guex,
SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling.
1997,
Pubmed
Hamill,
Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches.
1981,
Pubmed
Horrigan,
Coupling between voltage sensor activation, Ca2+ binding and channel opening in large conductance (BK) potassium channels.
2002,
Pubmed
Islas,
Voltage sensitivity and gating charge in Shaker and Shab family potassium channels.
1999,
Pubmed
James,
CryoEM structure of a prokaryotic cyclic nucleotide-gated ion channel.
2017,
Pubmed
James,
Structural insights into the mechanisms of CNBD channel function.
2018,
Pubmed
Kalstrup,
S4-S5 linker movement during activation and inactivation in voltage-gated K+ channels.
2018,
Pubmed
Kwan,
Structural changes during HCN channel gating defined by high affinity metal bridges.
2012,
Pubmed
,
Echinobase
Larsson,
Transmembrane movement of the shaker K+ channel S4.
1996,
Pubmed
Lee,
Structures of the Human HCN1 Hyperpolarization-Activated Channel.
2017,
Pubmed
Li,
Structure of a eukaryotic cyclic-nucleotide-gated channel.
2017,
Pubmed
Liman,
Subunit stoichiometry of a mammalian K+ channel determined by construction of multimeric cDNAs.
1992,
Pubmed
Long,
Voltage sensor of Kv1.2: structural basis of electromechanical coupling.
2005,
Pubmed
Long,
Crystal structure of a mammalian voltage-dependent Shaker family K+ channel.
2005,
Pubmed
Lu,
Coupling between voltage sensors and activation gate in voltage-gated K+ channels.
2002,
Pubmed
Lu,
Ion conduction pore is conserved among potassium channels.
2001,
Pubmed
Ludwig,
A family of hyperpolarization-activated mammalian cation channels.
1998,
Pubmed
Lörinczi,
Voltage-dependent gating of KCNH potassium channels lacking a covalent link between voltage-sensing and pore domains.
2015,
Pubmed
Mazzolini,
Gating in CNGA1 channels.
2010,
Pubmed
Männikkö,
Voltage-sensing mechanism is conserved among ion channels gated by opposite voltages.
2002,
Pubmed
,
Echinobase
Prole,
Reversal of HCN channel voltage dependence via bridging of the S4-S5 linker and Post-S6.
2006,
Pubmed
,
Echinobase
Robinson,
Hyperpolarization-activated cation currents: from molecules to physiological function.
2003,
Pubmed
Rothberg,
Voltage-controlled gating at the intracellular entrance to a hyperpolarization-activated cation channel.
2002,
Pubmed
,
Echinobase
Ryu,
Charge movement in gating-locked HCN channels reveals weak coupling of voltage sensors and gate.
2012,
Pubmed
,
Echinobase
Santoro,
Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain.
1998,
Pubmed
Santoro,
The HCN gene family: molecular basis of the hyperpolarization-activated pacemaker channels.
1999,
Pubmed
Shin,
Inactivation in HCN channels results from reclosure of the activation gate: desensitization to voltage.
2004,
Pubmed
Shin,
Blocker state dependence and trapping in hyperpolarization-activated cation channels: evidence for an intracellular activation gate.
2001,
Pubmed
,
Echinobase
Sun,
Cryo-EM Structure of a KCNQ1/CaM Complex Reveals Insights into Congenital Long QT Syndrome.
2017,
Pubmed
Tao,
Cryo-EM structure of the open high-conductance Ca2+-activated K+ channel.
2017,
Pubmed
Tomczak,
A new mechanism of voltage-dependent gating exposed by KV10.1 channels interrupted between voltage sensor and pore.
2017,
Pubmed
Vemana,
S4 movement in a mammalian HCN channel.
2004,
Pubmed
,
Echinobase
Wainger,
Molecular mechanism of cAMP modulation of HCN pacemaker channels.
2001,
Pubmed
Wang,
Cryo-EM Structure of the Open Human Ether-à-go-go-Related K+ Channel hERG.
2017,
Pubmed
Whicher,
Structure of the voltage-gated K⁺ channel Eag1 reveals an alternative voltage sensing mechanism.
2016,
Pubmed
Yifrach,
Energetics of pore opening in a voltage-gated K(+) channel.
2002,
Pubmed
Zagotta,
Structure and function of cyclic nucleotide-gated channels.
1996,
Pubmed
de la Peña,
Gating mechanism of Kv11.1 (hERG) K+ channels without covalent connection between voltage sensor and pore domains.
2018,
Pubmed
del Camino,
Tight steric closure at the intracellular activation gate of a voltage-gated K(+) channel.
2001,
Pubmed
del Camino,
Blocker protection in the pore of a voltage-gated K+ channel and its structural implications.
2000,
Pubmed
