Biophysical and Pharmacological Insights to CLC Chloride Channels

The CLC family encompasses two functional categories of transmembrane proteins: chloride conducting channels and proton-chloride antiporters. All members in this chloride channel/transporter family consist of two identical protein subunits, and each subunit forms an independent ion-transport pathway, a structural architecture known as “double barrel.” These CLC proteins serve biological functions ranging from membrane excitability and cell volume regulation to acidification of endosomes. Despite their ubiquitous expression, physiological significance, and resolved molecular structures of some of the family members, the mechanisms governing these molecules’ biophysical functions are still not completely settled. However, a series of functional and structural studies have brought insights into interesting questions related to these proteins. This chapter explores the functional peculiarities underlying CLC channels aided by information observed from the chloride-proton antiporters in the CLC family. The overall structural features of these CLC proteins will be presented, and the biophysical functions will be addressed. Finally, the mechanism of pharmacological agents that interact with CLC channels will also be discussed.