CLC Chloride Channels and Transporters: Structure, Function, Physiology, and Disease

Abstract

CLC anion transporters are found in all phyla and form a gene family of eight members in mammals. Two CLC proteins, each of which completely contains an ion translocation parthway, assemble to homo- or heteromeric dimers that sometimes require accessory β-subunits for function. CLC proteins come in two flavors: anion channels and anion/proton exchangers. Structures of these two CLC protein classes are surprisingly similar. Extensive structure-function analysis identified residues involved in ion permeation, anion-proton coupling and gating and led to attractive biophysical models. In mammals, ClC-1, -2, -Ka/-Kb are plasma membrane Cl channels, whereas ClC-3 through ClC-7 are 2Cl/H-exchangers in endolysosomal membranes. Biological roles of CLCs were mostly studied in mammals, but also in plants and model organisms like yeast and Caenorhabditis elegans. CLC Cl channels have roles in the control of electrical excitability, extra- and intracellular ion homeostasis, and transepithelial transport, whereas anion/proton exchangers influence vesicular ion composition and impinge on endocytosis and lysosomal function. The surprisingly diverse roles of CLCs are highlighted by human and mouse disorders elicited by mutations in their genes. These pathologies include neurodegeneration, leukodystrophy, mental retardation, deafness, blindness, myotonia, hyperaldosteronism, renal salt loss, proteinuria, kidney stones, male infertility, and osteopetrosis. In this review, emphasis is laid on biophysical structure-function analysis and on the cell biological and organismal roles of mammalian CLCs and their role in disease.

Drosophila ClC‐a is required in glia of the stem cell niche for proper neurogenesis and wiring of neural circuits

“…Among the ion channels expressed in glia, the vertebrate plasma‐membrane ClC‐2 chloride channel has been proposed as one of the channels involved in K + buffering, a key ionic homeostasis process in which glia are involved (Jentsch & Pusch, ; H. Wang et al, ). In the mature nervous system, increased neural activity leads to an increase in extracellular K + , which can alter neuronal excitability.…”

“…Among the ion channels expressed in glia, the vertebrate plasmamembrane ClC-2 chloride channel has been proposed as one of the channels involved in K + buffering, a key ionic homeostasis process in which glia are involved (Jentsch & Pusch, 2018;H. Wang et al, 2017).…”

Structural characterization of an intermediate reveals a unified mechanism for the CLC Cl−/H+ transport cycle

“…This putative inward-open state appears distinct from the conformational 14 change observed in the QQQ mutant, as the inter-residue distances for the cross-link pairs (399/432 15 and 399/259) are unchanged in QQQ relative to WT. The details of the kinetic-barrier and 16 conformational-change models, and the need for additional experiments on this aspect of transport, 17 have been clearly and comprehensively discussed (Accardi, 2015;Jentsch and Pusch, 2018). 18…”

“…CLC transporter proteins are present in intracellular compartments throughout our bodies -in 2 our hearts, brains, kidneys, liver, muscles, and guts -where they catalyze coupled exchange of 3 chloride (Cl -) for protons (H + ) (Jentsch and Pusch, 2018). Their physiological importance is 4 underscored by phenotypes observed in knockout animals, including severe neurodegeneration and 5 osteopetrosis (Sobacchi et al, 1993;Stobrawa et al, 2001;Hoopes et al, 2005;Kasper et al, 2005), 6 and by their links to human disease including X-linked mental retardation, epileptic seizures, Dent's 7 disease, and osteopetrosis (Lloyd et al, 1996;Hoopes et al, 2005;Veeramah et al, 2013;Hu et al, 8 2016).…”

Identification of TMEM206 proteins as pore of ASOR acid-sensitive chloride channels

“…Chloride channels fulfill a broad range of biological functions, including the homeostasis of cell volume, vesicular acidification, transepithelial transport and cellular signaling [1,2]. Elucidation of these roles has been greatly facilitated by the molecular identification of the underlying channel proteins, a discovery process that began in the late 1980's and is still ongoing.…”