Ion Channel Mechanisms in Cardiac and Cancer Pathophysiology

Ion channels regulate the selective flow of ions across cellular membranes, underpinning the electrical signalling that drives cardiac rhythm and modulating pathways that control cell proliferation, survival and migration in cancer. In the heart, voltage-gated potassium channels, notably the human Ether-à-go-go-Related Gene (hERG) channel, govern the repolarisation phase of the action potential; alterations in channel gating, trafficking or drug blockade can prolong repolarisation, precipitating arrhythmias and long QT syndromes. In oncology, aberrant expression and activity of channels such as the Eag1 (Kv10.1) and other members of the KCNH family confer proliferative advantages, inhibit apoptosis and promote angiogenesis. Recent advances in structural biology, computational modelling and patient-derived cellular systems have unveiled noncanonical electromechanical transduction pathways in cardiac channels, novel drug-binding determinants in pore domains and mechanistic links between ion fluxes and hypoxia signalling in tumours. By targeting specific structural motifs—such as the PAS domain in hERG or intracellular interfaces in Kv10.1—research is converging on precision therapies that restore normal cardiac electrophysiology or counteract malignant phenotypes. These interdisciplinary efforts highlight the global significance of ion channel biology as a nexus between fundamental biophysics and clinical translation.

Research from Nature Portfolio

Recent studies have illuminated how structural elements beyond the classical voltage-sensor–pore interface shape cardiac potassium channel function. A combined molecular dynamics and mutagenesis approach mapped a kinematic chain of residues linking the S4 voltage-sensor to the pore domain of hERG, revealing a non-canonical electromechanical pathway essential for activation and inactivation. In parallel, a detailed electrophysiological and computational investigation identified an aromatic residue in helix S5 (F557) as a high-affinity binding determinant for diverse blockers, expanding the established pharmacophore centred on S6 side chains and refining models for drug-channel interactions. Foundational work on the KCNH family showed that even in the absence of the covalent S4–S5 linker, voltage-dependent gating persists via alternative coupling routes, challenging prevailing paradigms of electromechanical transduction and suggesting new targets for modulating channel activity.

Ion Channel Mechanisms in Cardiac and Cancer Pathophysiology publication trend

The graph below shows the total number of articles in ion channel mechanisms in cardiac and cancer pathophysiology across all publications each year (not limited to Nature Index journals).

Technical terms

Voltage-gated potassium channel: A transmembrane protein that opens or closes in response to changes in membrane potential to conduct K⁺ ions.

Electromechanical coupling: The process by which voltage-sensor movements are translated into conformational changes that open or close the channel pore.

PAS domain: A conserved protein motif (Per-Arnt-Sim) in the hERG N-terminus that influences channel gating and inactivation.

hERG channel: A voltage-gated K⁺ channel encoded by the KCNH2 gene, critical for cardiac repolarisation and implicated in drug-induced arrhythmias.

Eag1 (Kv10.1) channel: A member of the KCNH family aberrantly expressed in many solid tumours, involved in proliferative and angiogenic signalling.

Action potential duration (APD): The interval during which a cardiac cell membrane remains depolarised before repolarisation is complete.

Early afterdepolarisation (EAD): Abnormal secondary depolarisations during repolarisation that can trigger arrhythmias.

References

1. Noncanonical electromechanical coupling paths in cardiac hERG potassium channel. Nature Communications (2023).
2. New potential binding determinant for hERG channel inhibitors. Scientific Reports (2016).
3. Voltage-dependent gating of KCNH potassium channels lacking a covalent link between voltage-sensing and pore domains. Nature Communications (2015).
4. Revealing a hidden conducting state by manipulating the intracellular domains in KV10.1 exposes the coupling between two gating mechanisms.. eLife (2024).
5. A PAS-targeting hERG1 activator reduces arrhythmic events in Jervell and Lange-Nielsen syndrome patient-derived hiPSC-CMs. JCI Insight (2025).
6. Novel roles for hERG K+ channels in cell proliferation and apoptosis. Cell Death & Disease (2011).
7. Overexpression of Eag1 potassium channels in clinical tumours. Molecular Cancer (2006).
8. Eag1 Expression Interferes with Hypoxia Homeostasis and Induces Angiogenesis in Tumors*. Journal of Biological Chemistry (2008).