For years, the chloride intracellular channel protein 6 (CLIC6) has been a protein of mystery. Recognized for its association with various cancers and interactions with dopamine receptors, CLIC6’s role as an ion channel remained elusive, with conflicting evidence from different studies.

CLIC6 is part of the distinctive family of non-canonical chloride intracellular channels (CLICs) exhibiting a unique feature that distinguishes them from other ion channels: they exist in two forms, soluble and transmembrane. While the soluble cytosolic form structure of most of the CLIC proteins is known, the membrane-bound form, particularly of CLIC6, still poses many questions. Despite its discovery over two decades ago and structural homology with other CLIC proteins, evidence of the ability of CLIC6 to form an ion channel was lacking, until now.

A recent study by the Harpreet Singh group, has finally shed light on the functionality of CLIC6. The researchers characterized the biophysical properties of the overexpressed CLIC6 in HEK293 cells using both manual and automated patch-clamp (the SyncroPatch 384i). They demonstrated that CLIC6 forms a functional channel with a conductance ∼3 pS and a rectification at positive holding potentials, which is unique to CLIC6 and is not observed for other CLIC family members. Another interesting finding is that CLIC6 was shown to be highly selective for chloride ions, unlike other CLIC members, known to form poorly selective ion channels. Delving deeper, CLIC6 was also found to be regulated by pH and redox potential. The study pinpointed specific histidine residue in the C terminus and cysteine residue in the N terminus as pivotal to the channel’s response to pH and redox changes.

Overall, this study established CLIC6 as a chloride-selective ion channel regulated by redox potential and pH – a significant advancement that enhances our understanding of this intriguing CLIC channel family.

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