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| Open AccessConformational trajectory of allosteric gating of the human cone photoreceptor cyclic nucleotide-gated channel
Hu et al. present eight cryo-EM structures of the human cone photoreceptor CNGA3/CNGB3 channel in the closed, intermediate, pre-open and open states, all fully bound with cGMP. These structures provide an unprecedented view of the conformational trajectory of CNG channel activation.
- Zhengshan Hu
- , Xiangdong Zheng
- & Jian Yang
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Article
| Open AccessGating intermediates reveal inhibitory role of the voltage sensor in a cyclic nucleotide-modulated ion channel
Visualizing conformational changes during ion channel gating is crucial to understand their regulation. Here, Gao et al. capture multiple gating intermediates in a CNG channel as well as subtle, lateral voltage sensor movements necessary for channel opening.
- Xiaolong Gao
- , Philipp A. M. Schmidpeter
- & Crina M. Nimigean
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Article
| Open AccessIon-dependent structure, dynamics, and allosteric coupling in a non-selective cation channel
NaK is a bacterial non-selective cation channel. Here, the authors use solution NMR to show that selectivity filter (SF) in NaK is dynamic, with structural differences between the Na+ and K + -bound states. The conformation of the SF is communicated to the pore-lining helices similarly as in the K + -selective channels.
- Adam Lewis
- , Vilius Kurauskas
- & Katherine Henzler-Wildman
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Article
| Open AccessElectromechanical coupling mechanism for activation and inactivation of an HCN channel
Sea urchin hyperpolarization-activated cyclic nucleotide-gated (spHCN) ion channels channels are activated by membrane hyperpolarization instead of depolarization and undergo inactivation with hyperpolarization. Here authors apply transition metal ion FRET, patch-clamp fluorometry and Rosetta modeling to measure differences in the structural rearrangements between activation and inactivation of spHCN channels.
- Gucan Dai
- , Teresa K. Aman
- & William N. Zagotta
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Article
| Open AccessProlyl isomerization controls activation kinetics of a cyclic nucleotide-gated ion channel
SthK, a cyclic nucleotide-gated ion channel from Spirochaeta thermophila activates slowly upon cAMP increase. Here, authors investigate cAMP-induced activation in purified SthK channels using stopped-flow assays and enzymatic catalysis and reveal that the cis/trans conformation of a conserved proline in the cyclic nucleotide-binding domain determines the activation kinetics of SthK.
- Philipp A. M. Schmidpeter
- , Jan Rheinberger
- & Crina M. Nimigean
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Article
| Open AccesscAMP-dependent regulation of HCN4 controls the tonic entrainment process in sinoatrial node pacemaker cells
The involvement of cAMP-dependent regulation of HCN4 in the chronotropic heart rate response is a matter of debate. Here the authors use a knockin mouse model expressing cAMP-insensitive HCN4 channels to discover an inhibitory nonfiring cell pool in the sinoatrial node and a tonic and mutual interaction between firing and nonfiring pacemaker cells that is controlled by cAMP-dependent regulation of HCN4, with implications in chronotropic heart rate responses.
- Stefanie Fenske
- , Konstantin Hennis
- & Christian Wahl-Schott
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| Open AccessConformational rearrangements in the transmembrane domain of CNGA1 channels revealed by single-molecule force spectroscopy
Cyclic nucleotide gated channels are activated after binding cyclic nucleotides. Here, using single molecule force spectroscopy, the authors reveal that cyclic nucleotide binding causes conformational changes and tighter coupling of the S4 helix to the pore forming domain.
- Sourav Maity
- , Monica Mazzolini
- & Vincent Torre
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Article
| Open AccessHysteresis of ligand binding in CNGA2 ion channels
Cyclic nucleotide-gated channels mediate olfactory and visual responses. Using a fluorescent cGMP derivative, Nache et al.show that the rate of cyclic nucleotide release from CNGA2 depends on the extent to which this tetrameric receptor is liganded, revealing hysteresis in the gating mechanism.
- Vasilica Nache
- , Thomas Eick
- & Klaus Benndorf
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Gating of cyclic nucleotide-gated channels is voltage dependent
Cyclic nucleotide-gated channels are apparently voltage insensitive despite having the S4-type voltage sensor. Marchesiet al.show that the gating of wild-type CNGA1 and native CNG channels is voltage-independent in the presence of Li+, Na+ and K+, but that it is voltage-dependent in the presence of Rb+, Cs+ and organic cations.
- Arin Marchesi
- , Monica Mazzolini
- & Vincent Torre
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Modulation of rod photoreceptor output by HCN1 channels is essential for regular mesopic cone vision
At light levels where both rods and cones are active, their signals converge into shared downstream retinal circuitry. Using HCN1 deficient mice, this study shows that the signals from cone photoreceptors are overwhelmed when rod output is not regulated, suggesting a mechanism for how these systems interact.
- Mathias W. Seeliger
- , Arne Brombas
- & Frank Müller
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Article
| Open AccessMolecular mechanism for 3:1 subunit stoichiometry of rod cyclic nucleotide-gated ion channels
The assembly mechanisms of heteromeric ion channels are poorly understood. Using a range of techniques, Shuartet al.determine the mechanism by which rod photoreceptor cyclic nucleotide-gated channels assume a 3:1 stoichiometry of CNGA1 and CNGB1 subunits.
- Noah G. Shuart
- , Yoni Haitin
- & William N. Zagotta