Regulatory–auxiliary subunits of CLC chloride channel–transport proteins

Abstract

The CLC family of chloride channels and transporters is composed by nine members, but only three of them, ClC-Ka/b, ClC-7 and ClC-2, have been found so far associated with auxiliary subunits. These CLC regulatory subunits are small proteins that present few common characteristics among them, both structurally and functionally, and their effects on the corresponding CLC protein are different. Barttin, a protein with two transmembrane domains, is essential for the membrane localization of ClC-K proteins and their activity in the kidney and inner ear. Ostm1 is a protein with a single transmembrane domain and a highly glycosylated N-terminus. Unlike the other two CLC auxiliary subunits, Ostm1 shows a reciprocal relationship with ClC-7 for their stability. The subcellular localization of Ostm1 depends on ClC-7 and not the other way around. ClC-2 is active on its own, but GlialCAM, a transmembrane cell adhesion molecule with two extracellular immunoglobulin (Ig)-like domains, regulates its subcellular localization and activity in glial cells. The common theme for these three proteins is their requirement for a proper homeostasis, since their malfunction leads to distinct diseases. We will review here their properties and their role in normal chloride physiology and the pathological consequences of their improper function.

Leukoencephalopathy‐causing CLCN2 mutations are associated with impaired Cl− channel function and trafficking

“…Our results provide additional evidence supporting the role of GlialCAM as a subunit for MLC1 or ClC‐2 (Barrallo‐Gimeno et al . ). In vitro and in vivo data have shown that MLC1 expression at the PM depends on GlialCAM.…”

“…In addition, GlialCAM restricts ClC‐2 localisation to cell–cell junctions and modulates ClC‐2 channel activity (Barrallo‐Gimeno & Estévez, ; Barrallo‐Gimeno et al . ). The latter is accomplished by increasing current amplitudes of ClC‐2, as well as changing the rectification and activation properties of the channel by affecting its common gating (Jeworutzki et al .…”

Twenty‐five years of CLC chloride transport proteins

“…Barrallo‐Gimeno and colleagues review the current state of knowledge regarding these auxiliary subunits: (1) Barttin, important for functionality and regulation of CLC‐K channels, (2) GlialCam, which modifies the physiology of its partner, the ubiquitously distributed CLC‐2, and (3) Ostm1, critical for CLC‐7 activity and stabilization (Barrallo‐Gimeno et al . ). Identified from analysis of genes linked to Bartter's syndrome (Birkenhäger et al .…”

A Short Guide to Electrophysiology and Ion Channels

“…To date, Barttin, Ostm1, GlialCAM are the three regulatory-auxiliary subunits of CLC chloride channel that have been identified (64). As an example, for comparison between these regulatory-auxiliary subunits of above mentioned CLC subfamily, Barttin and Ostm1 are required for endoplasmic reticulum exit, while GlialCAM is not necessary (64). Furthermore, recently it has been reported that palmitoylation of Barttin changes CLC-K channels into an active state (65).…”

“…So far, just three members of CLC family, ClC-Ka/b, ClC-7, and ClC-2, have been suggested to be linked with accessory subunits. To date, Barttin, Ostm1, GlialCAM are the three regulatory-auxiliary subunits of CLC chloride channel that have been identified (64). As an example, for comparison between these regulatory-auxiliary subunits of above mentioned CLC subfamily, Barttin and Ostm1 are required for endoplasmic reticulum exit, while GlialCAM is not necessary (64).…”