Chloride intracellular channel protein 5 (CLIC5)

Molecular Classification

Ion channel (intracellular chloride channel family), Other (has glutaredoxin-like thiol-disulfide exchange activity)

Other Names

CLIC5A, CLIC5B, p64, p62 (avian ortholog), Chloride intracellular channel 5

Disease Roles

Sensorineural deafness (autosomal recessive non-syndromic deafness, especially DFNB103)Glomerular disorders (glomerular podocyte injury, nephrotic syndrome)Cancer (role as prognostic biomarker and contribution to invasion/migration in hepatocellular carcinoma)

Chloride intracellular channel protein 5 Overview

Chloride intracellular channel protein 5 (CLIC5) is a member of the CLIC family of intracellular chloride channels. Unlike classical plasma membrane chloride channels, CLIC5 can transition between soluble and membrane-associated forms, enabling unique ion channel and enzymatic functions. It is highly expressed in specialized cells such as podocytes in the renal glomerulus and inner ear hair cells, where it is critical for maintaining cellular structure, facilitating actin-membrane interactions, and ensuring proper function of the filtration barrier and hearing apparatus. CLIC5 has at least two major isoforms (CLIC5A and CLIC5B) and interacts with cytoskeletal and membrane proteins such as ezrin and podocalyxin-like protein. Mutations or loss of CLIC5 function are associated with hearing loss and renal disease. Its roles in cancer and as a prognostic biomarker are emerging research areas. Pharmaceutical modulation of CLIC5 is limited by a lack of highly selective channel inhibitors and unresolved controversies about its precise physiological channel activity.

Mechanism of Action

Inhibition of chloride and cation conductance (IAA-94 and A9C) Inhibition of enzymatic/thiol-transferase activity (IAA-94 and A9C)

Biological Functions

Regulation of actin-based cytoskeleton structures

Cell architecture maintenance (e.g., podocyte and endothelial cell integrity)

Formation of stereocilia in cochlear hair cells (hearing)

Maintenance of glomerular filtration (renal physiology)

Cell membrane fusion (fusogenic activity)

Modulation of phosphorylation events impacting cytoskeleton-membrane coupling

Disease Associations

Sensorineural deafness (autosomal recessive non-syndromic deafness, especially DFNB103)

Glomerular disorders (glomerular podocyte injury, nephrotic syndrome)

Cancer (role as prognostic biomarker and contribution to invasion/migration in hepatocellular carcinoma)

Hypertension-induced glomerular injury

Safety Considerations

Disruption of CLIC5 function leads to hearing loss (due to stereocilia malformation and degeneration of hair cells)
Knock-out models show susceptibility to glomerular disease; there is a risk of renal dysfunction if targeted therapeutically
Notable for limited selectivity of known pharmacological inhibitors; can affect other intracellular chloride channels

Interacting Drugs

IAA-94 (chloride channel blocker)

4,4'-Diisothiocyanostilbene-2,2'-disulfonic acid (DIDS, not active on CLIC5)

9-Anthracenecarboxylic acid (A9C)

Associated Biomarkers

Biomarker
Co-expression with EZR and PODXL in hepatocellular carcinoma, used as a prognostic indicator
May be used with other podocyte markers in kidney injury/disease