ABSTRACT

CLC chloride channels and transporters are found throughout all forms of life, from bacteria to mammals. Roughly half of CLC family members are anion-selective channels, while the other half are secondary active transporters that exchange anions for protons. CLC channels operate as “degraded” transporters – they maintain key transporter characteristics (including coupling of protein conformational change to substrate binding, unbinding and translocation) but have lost the ability to stoichiometrically exchange substrates. Structurally, both CLC transporters and channels are homodimers, with the subunits containing independent pathways for ion permeation. The mechanism of voltage dependence in the CLCs differs markedly from that of cation-selective ion channels and arises from movement of the permeant ions rather than movement of charged domains on the protein. CLCs are critical to a wide variety of physiological processes, including skeletal muscle excitability, bone resorption, hearing and thinking.