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.

Figure 1

Proposed topologies for CLC regulatory subunits in the membrane A, Barttin. B, Ostm1. C, GlialCAM. The approximate position of some pathological mutations is indicated. For GlialCAM, dominant mutations are underlined.

Figure 2

Barttin and GlialCAM subunits affect the functional expression of ClC-K1 and ClC-2, respectively Typical current traces of oocytes expressing ClC-K1 or ClC-2 without and with their respective subunit in response to the IV protocols shown above the traces. A, WT ClC-K1 alone (left) and co-expressed with Barttin (right). B, WT ClC-2 alone (left) and co-expressed with GlialCAM (right).