HCN4

Last update 23 Jan 2025

Basic Info

Synonyms

HCN4, hyperpolarization activated cyclic nucleotide gated potassium channel 4, hyperpolarization activated cyclic nucleotide-gated potassium channel 4

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Introduction

Hyperpolarization-activated ion channel with very slow activation and inactivation exhibiting weak selectivity for potassium over sodium ions. Contributes to the native pacemaker currents in heart (If) that regulate the rhythm of heart beat. May contribute to the native pacemaker currents in neurons (Ih). May mediate responses to sour stimuli.

100 Clinical Results associated with HCN4

100 Translational Medicine associated with HCN4

0 Patents (Medical) associated with HCN4

771

Literatures (Medical) associated with HCN4

13 Dec 2024·ACS Pharmacology & Translational Science

Combination of Autodisplay and Dynamic Pharmacophore Modeling Reveals New Insights into Cyclic Nucleotide Binding in Hyperpolarization-Activated and Cyclic Nucleotide-Gated Ion Channel 4 (HCN4)

Article

Author: Wojciechowski, Magdalena N. ; Jose, Joachim ; Bermúdez, Marcel ; Jokiel, Johannes ; Kuss, Hanna

Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels play a critical role in regulating neuronal and cardiac rhythmicity, with their function being modulated by cyclic nucleotide binding. Dysfunction of HCN ion channels leads to the genesis of several diseases such as arrhythmia, bradycardia, or epilepsy. This study employs a multidisciplinary approach integrating mutagenesis, ligand binding assays, and molecular dynamics (MD) simulations combined with dynamic pharmacophore studies to investigate the impact of single residue mutations within the cyclic nucleotide-binding domain (CNBD) of HCN4 channels. Utilizing an autodisplay-based ligand binding assay, surface-displayed HCN4 CNBD mutants were evaluated for their interaction with 8-Fluo-cAMP, providing insights into the ligand binding properties. While some known mutational effects could be confirmed (R669, T670), we identified L652 to be crucial for successful ligand binding. Surprisingly, C662, located in the center of the binding pocket, was discovered to play a negligible role in cAMP-binding. Both E660 and R710 were shown to substantially affect 8-Fluo-cAMP-binding, uncovering the direct ligand binding capability of the R710A mutant for the first time. Furthermore, MD simulations coupled with dynamic pharmacophore analysis offered detailed insights into dynamic ligand-protein interactions, elucidating the structural basis of ligand binding and modulation induced by single residue mutations. Here, a novel bypass mechanism of R713 that interacts with cAMP in the absence of R710 was demonstrated. These findings unveil new perspectives on cyclic nucleotide binding in HCN4 channels, providing a foundation for future studies of pathogenic HCN4 ion channel mutations.

01 Dec 2024·Journal of Arrhythmia

Editorial to “Atrial standstill in a young patient with ischemic stroke associated with inheritance of a novel HCN4 mutation”

Author: Kondo, Hidekazu ; Takahashi, Naohiko

01 Dec 2024·Journal of Arrhythmia

Atrial standstill in a young patient with ischemic stroke associated with inheritance of a novel HCN4 mutation

Article

Author: Mahajan, Ajay U. ; Sabnis, Girish R. ; Anand, Abhinav B. ; Shah, Bhavik S.

We present a case of HCN4 gene mutation presenting with atrial standstill and stroke in the young.

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HCN4

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