Chloride Channel Physiology and Pathophysiology

Chloride channels constitute a widespread family of transmembrane proteins that mediate the selective passage of Cl− ions across cellular membranes. In mammals the CLC family comprises both voltage-gated chloride channels and Cl−/H+ exchangers that are finely tuned by membrane potential, pH and auxiliary subunits. These channels maintain resting membrane potential in skeletal muscle, facilitate transepithelial salt transport in kidney and inner ear, and regulate acid–base balance within endosomes, lysosomes and the Golgi apparatus. Gating mechanisms range from rapid ‘fast gates’ involving specific pore-lining residues to slower conformational changes of cytoplasmic domains. Genetic mutations or dysregulation of CLC proteins underlie a spectrum of human channelopathies, including myotonia congenita, Bartter’s syndrome, osteopetrosis, retinal degeneration and certain neurological disorders. Recent structural and functional studies have begun to map how alterations in pore architecture, ion affinity or subunit interaction translate into defective ion transport, informing therapeutic strategies for these diseases.

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Chloride Channel Physiology and Pathophysiology publication trend

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

Technical terms

Chloride channel: A membrane protein facilitating the selective diffusion of Cl− ions across lipid bilayers.

Voltage gating: A mechanism whereby changes in membrane potential control the opening and closing of ion channels.

Cryo-electron microscopy (cryo-EM): An imaging technique yielding near-atomic resolution structures of biomolecules in a frozen hydrated state.

Anion-proton exchanger: A transporter coupling the movement of Cl− ions with H+ to maintain ionic gradients and pH homeostasis.

CBS domains: Cytoplasmic cystathionine-β-synthase motifs that regulate CLC channel activity in response to nucleotides and pH changes.

References

1. ClC Channels and Transporters: Structure, Physiological Functions, and Implications in Human Chloride Channelopathies. Frontiers in Pharmacology (2017).
2. CryoEM structures of the human CLC-2 voltage-gated chloride channel reveal a ball-and-chain gating mechanism. eLife (2024).
3. Cryo-EM structure of the lysosomal chloride-proton exchanger CLC-7 in complex with OSTM1. eLife (2020).
4. Structure of the CLC-1 chloride channel from Homo sapiens. eLife (2018).