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
2021 Sep 14;11837:. doi: 10.1073/pnas.2102036118.
Show Gene links
Show Anatomy links
A second S4 movement opens hyperpolarization-activated HCN channels.
Wu X
,
Ramentol R
,
Perez ME
,
Noskov SY
,
Larsson HP
.
???displayArticle.abstract???
Rhythmic activity in pacemaker cells, as in the sino-atrial node in the heart, depends on the activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. As in depolarization-activated K+ channels, the fourth transmembrane segment S4 functions as the voltage sensor in hyperpolarization-activated HCN channels. But how the inward movement of S4 in HCN channels at hyperpolarized voltages couples to channel opening is not understood. Using voltage clamp fluorometry, we found here that S4 in HCN channels moves in two steps in response to hyperpolarizations and that the second S4 step correlates with gate opening. We found a mutation in sea urchin HCN channels that separate the two S4 steps in voltage dependence. The E356A mutation in S4 shifts the main S4 movement to positive voltages, but channel opening remains at negative voltages. In addition, E356A reveals a second S4 movement at negative voltages that correlates with gate opening. Cysteine accessibility and molecular models suggest that the second S4 movement opens up an intracellular crevice between S4 and S5 that would allow radial movement of the intracellular ends of S5 and S6 to open HCN channels.
Barro-Soria,
KCNE1 divides the voltage sensor movement in KCNQ1/KCNE1 channels into two steps.
2014, Pubmed
Barro-Soria,
KCNE1 divides the voltage sensor movement in KCNQ1/KCNE1 channels into two steps.
2014,
Pubmed
Barro-Soria,
KCNE1 and KCNE3 modulate KCNQ1 channels by affecting different gating transitions.
2017,
Pubmed
Bell,
Changes in local S4 environment provide a voltage-sensing mechanism for mammalian hyperpolarization-activated HCN channels.
2004,
Pubmed
Best,
Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone φ, ψ and side-chain χ(1) and χ(2) dihedral angles.
2012,
Pubmed
Biel,
Hyperpolarization-activated cation channels: from genes to function.
2009,
Pubmed
Brown,
How does adrenaline accelerate the heart?
1979,
Pubmed
Bruening-Wright,
Kinetic relationship between the voltage sensor and the activation gate in spHCN channels.
2007,
Pubmed
,
Echinobase
Chaplan,
Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain.
2003,
Pubmed
Cowgill,
Bipolar switching by HCN voltage sensor underlies hyperpolarization activation.
2019,
Pubmed
Dai,
The HCN channel voltage sensor undergoes a large downward motion during hyperpolarization.
2019,
Pubmed
,
Echinobase
DiFrancesco,
Direct activation of cardiac pacemaker channels by intracellular cyclic AMP.
1991,
Pubmed
Flynn,
Insights into the molecular mechanism for hyperpolarization-dependent activation of HCN channels.
2018,
Pubmed
,
Echinobase
Gauss,
Molecular identification of a hyperpolarization-activated channel in sea urchin sperm.
1998,
Pubmed
,
Echinobase
Grabe,
Structure prediction for the down state of a potassium channel voltage sensor.
2007,
Pubmed
Jo,
CHARMM-GUI Membrane Builder for mixed bilayers and its application to yeast membranes.
2009,
Pubmed
Kasimova,
Helix breaking transition in the S4 of HCN channel is critical for hyperpolarization-dependent gating.
2019,
Pubmed
Khalili-Araghi,
Calculation of the gating charge for the Kv1.2 voltage-activated potassium channel.
2010,
Pubmed
Klauda,
Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types.
2010,
Pubmed
Lai,
The S4 voltage sensor packs against the pore domain in the KAT1 voltage-gated potassium channel.
2005,
Pubmed
Larsson,
Transmembrane movement of the shaker K+ channel S4.
1996,
Pubmed
Ledwell,
Mutations in the S4 region isolate the final voltage-dependent cooperative step in potassium channel activation.
1999,
Pubmed
Lee,
Structures of the Human HCN1 Hyperpolarization-Activated Channel.
2017,
Pubmed
Lee,
Voltage Sensor Movements during Hyperpolarization in the HCN Channel.
2019,
Pubmed
Liu,
Gated access to the pore of a voltage-dependent K+ channel.
1997,
Pubmed
Long,
Crystal structure of a mammalian voltage-dependent Shaker family K+ channel.
2005,
Pubmed
Long,
Voltage sensor of Kv1.2: structural basis of electromechanical coupling.
2005,
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
Marini,
HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond.
2018,
Pubmed
Mayer,
A voltage-clamp analysis of inward (anomalous) rectification in mouse spinal sensory ganglion neurones.
1983,
Pubmed
Männikkö,
Voltage-sensing mechanism is conserved among ion channels gated by opposite voltages.
2002,
Pubmed
,
Echinobase
Nof,
Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia.
2007,
Pubmed
Phillips,
Scalable molecular dynamics with NAMD.
2005,
Pubmed
Phillips,
Scalable molecular dynamics on CPU and GPU architectures with NAMD.
2020,
Pubmed
Ramentol,
Gating mechanism of hyperpolarization-activated HCN pacemaker channels.
2020,
Pubmed
Ranganathan,
Spatial localization of the K+ channel selectivity filter by mutant cycle-based structure analysis.
1996,
Pubmed
Rothberg,
Voltage-controlled gating at the intracellular entrance to a hyperpolarization-activated cation channel.
2002,
Pubmed
,
Echinobase
Roux,
Influence of the membrane potential on the free energy of an intrinsic protein.
1997,
Pubmed
Roux,
The membrane potential and its representation by a constant electric field in computer simulations.
2008,
Pubmed
Ryu,
Charge movement in gating-locked HCN channels reveals weak coupling of voltage sensors and gate.
2012,
Pubmed
,
Echinobase
Sartiani,
The Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: from Biophysics to Pharmacology of a Unique Family of Ion Channels.
2017,
Pubmed
Schulze-Bahr,
Pacemaker channel dysfunction in a patient with sinus node disease.
2003,
Pubmed
Shin,
Blocker state dependence and trapping in hyperpolarization-activated cation channels: evidence for an intracellular activation gate.
2001,
Pubmed
,
Echinobase
Stieber,
Pacemaker channels and sinus node arrhythmia.
2004,
Pubmed
Strauss,
An impaired neocortical Ih is associated with enhanced excitability and absence epilepsy.
2004,
Pubmed
Sun,
Inhibition of hyperpolarization-activated current by ZD7288 suppresses ectopic discharges of injured dorsal root ganglion neurons in a rat model of neuropathic pain.
2005,
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