ClC Channels and Transporters: Structure, Physiological Functions, and Implications in Human Chloride Channelopathies

Abstract

The discovery of ClC proteins at the beginning of the 1990s was important for the development of the Cl- transport research field. ClCs form a large family of proteins that mediate voltage-dependent transport of Cl- ions across cell membranes. They are expressed in both plasma and intracellular membranes of cells from almost all living organisms. ClC proteins form transmembrane dimers, in which each monomer displays independent ion conductance. Eukaryotic members also possess a large cytoplasmic domain containing two CBS domains, which are involved in transport modulation. ClC proteins function as either Cl- channels or Cl-/H+ exchangers, although all ClC proteins share the same basic architecture. ClC channels have two gating mechanisms: a relatively well-studied fast gating mechanism, and a slow gating mechanism, which is poorly defined. ClCs are involved in a wide range of physiological processes, including regulation of resting membrane potential in skeletal muscle, facilitation of transepithelial Cl- reabsorption in kidneys, and control of pH and Cl- concentration in intracellular compartments through coupled Cl-/H+ exchange mechanisms. Several inherited diseases result from C1C gene mutations, including myotonia congenita, Bartter’s syndrome (types 3 and 4), Dent’s disease, osteopetrosis, retinal degeneration, and lysosomal storage diseases. This review summarizes general features, known or suspected, of ClC structure, gating and physiological functions. We also discuss biophysical properties of mammalian ClCs that are directly involved in the pathophysiology of several human inherited disorders, or that induce interesting phenotypes in animal models.

The Integral Role of Tight Junction Proteins in the Repair of Injured Intestinal Epithelium

“…The primary protein responsible for chloride transport into the intestinal lumen is the apically located cystic fibrosis transmembrane receptor (CFTR) [71]. However, another contributor to transepithelial chloride transport within intestinal epithelium is the voltage-gated ClC-2 protein, one of nine mammalian proteins belonging to the chloride channel (ClC) protein family [72]. ClC-2 has been shown to localize in the plasma membrane at tight junction complexes within mouse intestinal epithelium [73] or has plasmalemmal basolateral localization within guinea pig colons [74], suggesting species-or tissue-specific localization of ClC-2.…”

The chloride anion as a signalling effector

“…Clearly, a deep understanding of the mechanisms involved in protein and gene regulation by Cl − is important to understand better the pathologies associated with different Cl − channels (channelopathies) (Statland, Phillips & Trivedi, 2014;Suetterlin, Mannikko & Hanna, 2014;Poroca, Pelis Menegazzi et al (2000) & Chappe, 2017). The role of Cl − channels in disease has been extensively reviewed elsewhere (Kunzelmann & Mall, 2002;Pedemonte & Galietta, 2014;Hoffmann et al, 2015;Abeyrathne, Chami & Stahlberg, 2016;Ito, 2016;Whitlock & Hartzell, 2016;Poroca et al, 2017;Kamaleddin, 2018). The early history of the role of Cl − in muscle was recently reviewed by Hutter (2017).…”

Injection of mRNA isolated from trophozoites of Giardia intestinalis induces expression of three types of chloride currents in Xenopus laevis oocytes.

“…So far, several types of chloride channels have been identified, either by its molecular or its functional properties, including voltage‐dependent chloride channels (ClC),cystic fibrosis transmembrane regulator (CFTR), calcium‐activated chloride channels (CaCC), and volume‐regulated chloride channels (VRAC) (Poroca et al. ; Jentsch ; Grinstein et al. ).…”

“…Chloride channels have been found to be expressed in all types of cells, both in prokaryotes and in eukaryotes, participating in a wide variety of physiological processes, including excitability, cell proliferation, motility, cell volume regulation, and cellular recognition of their environment, among many others (Nilius and Droogmans 2003). So far, several types of chloride channels have been identified, either by its molecular or its functional properties, including voltage-dependent chloride channels (ClC),cystic fibrosis transmembrane regulator (CFTR), calcium-activated chloride channels (CaCC), and volume-regulated chloride channels (VRAC) (Poroca et al 2017;Jentsch 1996;Grinstein et al 1982). Although they have been described in almost all types of cells and tissues, there are only a few reports describing chloride channels in protozoans (Delgadillo et al 2002;Salas-Casas et al 2006;Moreno-Galindo et al 2014).…”