ArticleThe Journal of general physiology2017
The intrinsically liganded cyclic nucleotide-binding homology domain promotes KCNH channel activation.
Article in The Journal of general physiology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 37 citations in OpenAlex.
- Forward genetics reveals a conserved CNBHD-CNBHD interface that restrains EAG channel activation to regulate sleep.PLoS genetics · 2026Article
- Chlorpromazine inhibits EAG1 channels by altering the interdomain coupling.Biophysical journal · 2026Article
- Molecular Determinants of Voltage-Dependent Gating in Kv11.1 Channels.Advances in experimental medicine and biology · 2026Review
- An Allosteric Model for Electromechanical Coupling in Cardiac CNBD Channels.bioRxiv : the preprint server for biology · 2025Article
- GORK KNature communications · 2025Article
- Article
- Conformation-sensitive antibody reveals an altered cytosolic PAS/CNBh assembly during hERG channel gating.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Gating and regulation of KCNH (ERG, EAG, and ELK) channels by intracellular domains.Channels (Austin, Tex.) · 2020Review
- Structure of KCNH2 cyclic nucleotide-binding homology domain reveals a functionally vital salt-bridge.The Journal of general physiology · 2020Article
- Chlorpromazine binding to the PAS domains uncovers the effect of ligand modulation on EAG channel activity.The Journal of biological chemistry · 2020Article
- hERG Function in Light of Structure.Biophysical journal · 2020Review
- The EAG Voltage-Dependent KFrontiers in pharmacology · 2020Review
- Modulation of hERG KFrontiers in pharmacology · 2020Review
- Functional study of a KCNH2 mutant: Novel insights on the pathogenesis of the LQT2 syndrome.Journal of cellular and molecular medicine · 2019Article
- The hERG potassium channel intrinsic ligand regulates N- and C-terminal interactions and channel closure.The Journal of general physiology · 2019Article
- N- and C-terminal interactions in KCNH channels: The spotlight on the intrinsic ligand.The Journal of general physiology · 2019Article
- New Structures and Gating of Voltage-Dependent Potassium (Kv) Channels and Their Relatives: A Multi-Domain and Dynamic Question.International journal of molecular sciences · 2019Review
- Relative positioning of Kv11.1 (hERG) KScientific reports · 2018Article
- Dynamic rearrangement of the intrinsic ligand regulates KCNH potassium channels.The Journal of general physiology · 2018Article
- How an intrinsic ligand tunes the activity of a potassium channel.The Journal of general physiology · 2018Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Channels in the ether-à-go-go or KCNH family of potassium channels are characterized by a conserved, C-terminal domain with homology to cyclic nucleotide-binding homology domains (CNBhDs). Instead of cyclic nucleotides, two amino acid residues, Y699 and L701, occupy the binding pocket, forming an "intrinsic ligand." The role of the CNBhD in KCNH channel gating is still unclear, however, and a detailed characterization of the intrinsic ligand is lacking. In this study, we show that mutating both Y699 and L701 to alanine, serine, aspartate, or glycine impairs human EAG1 channel function. These mutants slow channel activation and shift the conductance-voltage (G-V) relation to more depolarized potentials. The mutations affect activation and the G-V relation progressively, indicating that the gating machinery is sensitive to multiple conformations of the CNBhD. Substitution with glycine at both sites (GG), which eliminates the side chains that interact with the binding pocket, also reduces the ability of voltage prepulses to populate more preactivated states along the activation pathway (i.e., the Cole-Moore effect), as if stabilizing the voltage sensor in deep resting states. Notably, deletion of the entire CNBhD (577-708, ΔCNBhD) phenocopies the GG mutant, suggesting that GG is a loss-of-function mutation and the CNBhD requires an intrinsic ligand to exert its functional effects. We developed a kinetic model for both wild-type and ΔCNBhD mutant channels that describes all our observations on activation kinetics, the Cole-Moore shift, and G-V relations. These findings support a model in which the CNBhD both promotes voltage sensor activation and stabilizes the open pore. The intrinsic ligand is critical for these functional effects.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.