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Structural biology and molecular pharmacology of voltage-gated ion channels

Nature Reviews Molecular Cell Biology (2024)Cite this article

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Abstract

Voltage-gated ion channels (VGICs), including those for Na+, Ca2+ and K+, selectively permeate ions across the cell membrane in response to changes in membrane potential, thus participating in physiological processes involving electrical signalling, such as neurotransmission, muscle contraction and hormone secretion. Aberrant function or dysregulation of VGICs is associated with a diversity of neurological, psychiatric, cardiovascular and muscular disorders, and approximately 10% of FDA-approved drugs directly target VGICs. Understanding the structure–function relationship of VGICs is crucial for our comprehension of their working mechanisms and role in diseases. In this Review, we discuss how advances in single-particle cryo-electron microscopy have afforded unprecedented structural insights into VGICs, especially on their interactions with clinical and investigational drugs. We present a comprehensive overview of the recent advances in the structural biology of VGICs, with a focus on how prototypical drugs and toxins modulate VGIC activities. We explore how these structures elucidate the molecular basis for drug actions, reveal novel pharmacological sites, and provide critical clues to future drug discovery.

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Fig. 1: Architecture and classification of voltage-gated ion channels.
Fig. 2: Structural basis for ion selectivity.
Fig. 3: Electromechanical coupling in voltage-gated ion channels.
Fig. 4: Multiple inactivation mechanisms for voltage-gated ion channels.
Fig. 5: Structural mapping of drug binding sites on Nav, Cav and Kv channels.

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Acknowledgements

The authors thank C. Song, Z. Li, G. Yang, S. Gao, X. Yao and H. Shen for their critical reading and input. We apologize to those whose remarkable contributions are not cited, constrained by page limitations. This work was funded by the National Natural Science Foundation of China (32330052, 32322039 and 32271252). N.Y. has been supported by the start-up funds of the University Professorship from Tsinghua University.

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Authors and Affiliations

  1. Department of Molecular Biology, Princeton University, Princeton, NJ, USA

    Jian Huang

  2. Institute of Bio-Architecture and Bio-Interactions (IBABI), Shenzhen Medical Academy of Research and Translation (SMART), Shenzhen, Guangdong, China

    Xiaojing Pan & Nieng Yan

  3. Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, State Key Laboratory of Membrane Biology, Tsinghua University, Beijing, China

    Nieng Yan

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Glossary

Ï€ helix

A secondary protein structure, characterized by hydrogen bonding between the amide group of a residue with the carbonyl oxygen five residues earlier (i + 5 → i) in a helix, resulting in a bulge in a typical α helix.

310 helix

A secondary protein structure with three residues and ten backbone atoms in each helical turn, characterized by hydrogen bonding between residues i + 3 → i.

Cation–π interaction

A type of noncovalent electrostatic interaction between a positive charge (cation) and the electron-rich aromatic π system.

Chirality

The geometric property of a molecule or object that cannot be superposed onto its mirror image.

Current–voltage (I–V) curve

A curve that depicts the relationship between the electric current, corresponding to ion flow, through the channels and the applied voltages.

Dihydropyridine

(DHP). A class of chemical compounds that can act as chirality-specific antagonists or agonists on the L-type calcium channels. Many DHP compounds are in clinical use as calcium channel blockers.

Hydration shell

A ‘hydration shell’ or ‘water shell’ refers to a continuous cluster of water molecules surrounding and, to a degree, attached to certain chemicals or biomolecules when they are dissolved in an aqueous solution.

Membrane depolarization

Shift in membrane potential reducing negative intracellular charges, mainly caused by cation influx or anion efflux.

Membrane potentials

The difference in electric charge, or voltage, between the interior and exterior of a cell or an organelle.

Molecular dynamic simulation (MDS) analysis

A computer simulation method that predicts the movements of atoms over time based on physical models for interatomic interactions.

Protein internal packing

The arrangement and interactions of amino acid residues within the three-dimensional structure of a protein, which are crucial for the stability, function and overall shape of the protein.

Resting state

The relatively stable state with regard to the membrane potential of an excitable cell, such as a neuron or a muscle cell.

Saxitoxin

(STX). The best-known paralytic shellfish toxin. It acts as a potent neurotoxin by blocking Nav channels.

Tetrodotoxin

(TTX). A potent guanidinium neurotoxin found in some fish and other species, exemplified by pufferfish. It specifically blocks Nav channels with different potencies.

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Huang, J., Pan, X. & Yan, N. Structural biology and molecular pharmacology of voltage-gated ion channels. Nat Rev Mol Cell Biol (2024). https://doi.org/10.1038/s41580-024-00763-7

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