Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Biol Chem
2020 Jun 12;29524:8164-8173. doi: 10.1074/jbc.RA120.013281.
Show Gene links
Show Anatomy links
The HCN domain is required for HCN channel cell-surface expression and couples voltage- and cAMP-dependent gating mechanisms.
Wang ZJ
,
Blanco I
,
Hayoz S
,
Brelidze TI
.
???displayArticle.abstract???
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are major regulators of synaptic plasticity and rhythmic activity in the heart and brain. Opening of HCN channels requires membrane hyperpolarization and is further facilitated by intracellular cyclic nucleotides (cNMPs). In HCN channels, membrane hyperpolarization is sensed by the membrane-spanning voltage sensor domain (VSD), and the cNMP-dependent gating is mediated by the intracellular cyclic nucleotide-binding domain (CNBD) connected to the pore-forming S6 transmembrane segment via the C-linker. Previous functional analysis of HCN channels has suggested a direct or allosteric coupling between the voltage- and cNMP-dependent activation mechanisms. However, the specifics of this coupling remain unclear. The first cryo-EM structure of an HCN1 channel revealed that a novel structural element, dubbed the HCN domain (HCND), forms a direct structural link between the VSD and C-linker-CNBD. In this study, we investigated the functional significance of the HCND. Deletion of the HCND prevented surface expression of HCN2 channels. Based on the HCN1 structure analysis, we identified Arg237 and Gly239 residues on the S2 of the VSD that form direct interactions with Ile135 on the HCND. Disrupting these interactions abolished HCN2 currents. We also identified three residues on the C-linker-CNBD (Glu478, Gln482, and His559) that form direct interactions with residues Arg154 and Ser158 on the HCND. Disrupting these interactions affected both voltage- and cAMP-dependent gating of HCN2 channels. These findings indicate that the HCND is necessary for the cell-surface expression of HCN channels and provides a functional link between voltage- and cAMP-dependent mechanisms of HCN channel gating.
Akhavan,
Identification of the cyclic-nucleotide-binding domain as a conserved determinant of ion-channel cell-surface localization.
2005, Pubmed
Akhavan,
Identification of the cyclic-nucleotide-binding domain as a conserved determinant of ion-channel cell-surface localization.
2005,
Pubmed
Chen,
The S4-S5 linker couples voltage sensing and activation of pacemaker channels.
2001,
Pubmed
,
Xenbase
Cowgill,
Bipolar switching by HCN voltage sensor underlies hyperpolarization activation.
2019,
Pubmed
,
Xenbase
Craven,
Salt bridges and gating in the COOH-terminal region of HCN2 and CNGA1 channels.
2004,
Pubmed
,
Xenbase
Dai,
The HCN channel voltage sensor undergoes a large downward motion during hyperpolarization.
2019,
Pubmed
DiFrancesco,
Recessive loss-of-function mutation in the pacemaker HCN2 channel causing increased neuronal excitability in a patient with idiopathic generalized epilepsy.
2011,
Pubmed
DiFrancesco,
Pacemaker mechanisms in cardiac tissue.
1993,
Pubmed
DiFrancesco,
Direct activation of cardiac pacemaker channels by intracellular cyclic AMP.
1991,
Pubmed
DiFrancesco,
The role of the funny current in pacemaker activity.
2010,
Pubmed
Dibbens,
Augmented currents of an HCN2 variant in patients with febrile seizure syndromes.
2010,
Pubmed
,
Xenbase
Flynn,
Insights into the molecular mechanism for hyperpolarization-dependent activation of HCN channels.
2018,
Pubmed
Gianulis,
Direct interaction of eag domains and cyclic nucleotide-binding homology domains regulate deactivation gating in hERG channels.
2013,
Pubmed
Hummert,
Activation gating in HCN2 channels.
2018,
Pubmed
,
Xenbase
Jackson,
Identification of a consensus motif for retention of transmembrane proteins in the endoplasmic reticulum.
1990,
Pubmed
Kasimova,
Helix breaking transition in the S4 of HCN channel is critical for hyperpolarization-dependent gating.
2019,
Pubmed
Kaupp,
Molecular diversity of pacemaker ion channels.
2001,
Pubmed
King,
ngLOC: an n-gram-based Bayesian method for estimating the subcellular proteomes of eukaryotes.
2007,
Pubmed
Kusch,
Interdependence of receptor activation and ligand binding in HCN2 pacemaker channels.
2010,
Pubmed
,
Xenbase
Kwan,
Structural changes during HCN channel gating defined by high affinity metal bridges.
2012,
Pubmed
Lee,
Structures of the Human HCN1 Hyperpolarization-Activated Channel.
2017,
Pubmed
Lee,
Voltage Sensor Movements during Hyperpolarization in the HCN Channel.
2019,
Pubmed
Ludwig,
A family of hyperpolarization-activated mammalian cation channels.
1998,
Pubmed
Much,
Role of subunit heteromerization and N-linked glycosylation in the formation of functional hyperpolarization-activated cyclic nucleotide-gated channels.
2003,
Pubmed
Möller,
In Vitro Analyses of Novel HCN4 Gene Mutations.
2018,
Pubmed
,
Xenbase
Nakamura,
Novel HCN2 mutation contributes to febrile seizures by shifting the channel's kinetics in a temperature-dependent manner.
2013,
Pubmed
Nava,
De novo mutations in HCN1 cause early infantile epileptic encephalopathy.
2014,
Pubmed
Nilsson,
Short cytoplasmic sequences serve as retention signals for transmembrane proteins in the endoplasmic reticulum.
1989,
Pubmed
Pan,
An N-Terminal ER Export Signal Facilitates the Plasma Membrane Targeting of HCN1 Channels in Photoreceptors.
2015,
Pubmed
,
Xenbase
Porro,
The HCN domain couples voltage gating and cAMP response in hyperpolarization-activated cyclic nucleotide-gated channels.
2019,
Pubmed
Proenza,
Different roles for the cyclic nucleotide binding domain and amino terminus in assembly and expression of hyperpolarization-activated, cyclic nucleotide-gated channels.
2002,
Pubmed
Puljung,
Double electron-electron resonance reveals cAMP-induced conformational change in HCN channels.
2014,
Pubmed
Santoro,
Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain.
1998,
Pubmed
,
Xenbase
Santoro,
Molecular and functional heterogeneity of hyperpolarization-activated pacemaker channels in the mouse CNS.
2000,
Pubmed
,
Xenbase
Schulze-Bahr,
Pacemaker channel dysfunction in a patient with sinus node disease.
2003,
Pubmed
Shi,
Distribution and prevalence of hyperpolarization-activated cation channel (HCN) mRNA expression in cardiac tissues.
1999,
Pubmed
Shin,
Blocker state dependence and trapping in hyperpolarization-activated cation channels: evidence for an intracellular activation gate.
2001,
Pubmed
Tang,
Mutation analysis of the hyperpolarization-activated cyclic nucleotide-gated channels HCN1 and HCN2 in idiopathic generalized epilepsy.
2008,
Pubmed
,
Xenbase
Wahl-Schott,
HCN channels: structure, cellular regulation and physiological function.
2009,
Pubmed
Wainger,
Molecular mechanism of cAMP modulation of HCN pacemaker channels.
2001,
Pubmed
Wicks,
Sensitivity of HCN channel deactivation to cAMP is amplified by an S4 mutation combined with activation mode shift.
2009,
Pubmed
,
Xenbase
Zagotta,
Structural basis for modulation and agonist specificity of HCN pacemaker channels.
2003,
Pubmed
