George AL et al. (2001) Curr Biol "From stones to bones: the biology of ClC channels."

Link EM, Bianchi L, George AL, Vanoye CG

[Curr Biol, 2001]

Chloride (Cl-) is the most abundant extracellular anion in multicellular organisms. Passive movement of Cl- through membrane ion channels enables several cellular and physiological processes including transepithelial salt transport, electrical excitability, cell volume regulation and acidification of internal and external compartments. One family of proteins mediating Cl- permeability, the CIC channels, has emerged as important for all of these biological processes. The importance of CIC channels has in part been realized through studies of inherited human diseases and genetically engineered mice that display a wide range of phenotypes from kidney stones to petrified bones. These recent findings have demonstrated many eclectic functions of CIC channels and have placed Cl- channels in the physiological limelight.

Wolstenholme AJ (1997) Biochem Soc Trans "Glutamate-gated Cl- channels in Caenorhabditis elegans and parasitic nematodes."

Wolstenholme AJ

[Biochem Soc Trans, 1997]

Excitatory ionotropic and metabotropic glutamate receptors are found throughout the animal kingdom, but inhibitory ionotropic glutamate receptors seem to be confined to invertebrates. Molecular studies on all invertebrate receptors have lagged far behind those of their mammalian counterparts, but recently interest in the glutamate-gated Cl- channels (Glu-Cl) has been greatly stimulated by the discovery that, at least in Caenorhabditis elegans, these molecules act as the receptor for, and probable site of action of, the avermectins, a family of potent anthelminthics, insecticides and acaricides.

Kahle KT et al. (2010) Biochim Biophys Acta "Phosphoregulation of the Na-K-2Cl and K-Cl cotransporters by the WNK kinases."

Lifton RP, Kahle KT, Rinehart J

[Biochim Biophys Acta, 2010]

Precise regulation of the intracellular concentration of chloride [Cl-]i is necessary for proper cell volume regulation, transepithelial transport, and GABA neurotransmission. The Na-K-2Cl (NKCCs) and K-Cl (KCCs) cotransporters, related SLC12A transporters mediating cellular chloride influx and efflux, respectively, are key determinants of [Cl-]i in numerous cell types, including red blood cells, epithelial cells, and neurons. A common "chloride/volume-sensitive kinase", or related system of kinases, has long been hypothesized to mediate the reciprocal but coordinated phosphoregulation of the NKCCs and the KCCs, but the identity of these kinase(s) has remained unknown. Recent evidence suggests that the WNK (with no lysine = K) serine-threonine kinases directly or indirectly via the downstream Ste20-type kinases SPAK/OSR1, are critical components of this signaling pathway. Hypertonic stress (cell shrinkage), and possibly decreased [Cl-]i, triggers the phosphorylation and activation of specific WNKs, promoting NKCC activation and KCC inhibition via net transporter phosphorylation. Silencing WNK kinase activity can promote NKCC inhibition and KCC activation via net transporter dephosphorylation, revealing a dynamic ability of the WNKs to modulate [Cl-]. This pathway is essential for the defense of cell volume during osmotic perturbation, coordination of epithelial transport, and gating of sensory information in the peripheral system. Commiserate with their importance in serving these critical roles in humans, mutations in WNKs underlie two different Mendelian diseases, pseudohypoaldosteronism type II (an inherited form of salt-sensitive hypertension), and hereditary sensory and autonomic neuropathy type 2. WNKs also regulate ion transport in lower multicellular organisms, including Caenorhabditis elegans, suggesting that their functions are evolutionarily-conserved. An increased understanding of how the WNKs regulate the Na-K-2Cl and K-Cl cotransporters may provide novel opportunities for the selective modulation of these transporters, with ramifications for common human diseases like hypertension, sickle cell disease, neuropathic pain, and epilepsy.

Strange K et al. (2006) Physiology (Bethesda) "Ste20-type kinases: evolutionarily conserved regulators of ion transport and cell volume."

Nehrke K, Denton J, Strange K

[Physiology (Bethesda), 2006]

Ste20 serine/threonine kinases regulate fundamental cellular processes including the cell cycle, apoptosis, and stress responses. Recent studies in Caenorhabditis elegans and mammals demonstrate that Ste20 kinases also function in cell volume sensing and Cl- transport regulation. Yeast Ste20 initiates a shrinkage activated MAPK cascade that regulates organic osmolyte accumulation. Ste20 kinases thus play evolutionarily conserved roles in cellular volume sensing and regulation. They may also function in systemic osmotic homeostasis and to link cell-cycle events with cell volume.

Martin RJ (1993) Pharmacol Ther "Neuromuscular transmission in nematode parasites and antinematodal drug action."

Martin RJ

[Pharmacol Ther, 1993]

Some anthelmintic drugs interfere selectively with nematode neuromuscular transmission. These drugs include: the nicotinic agonists, e.g. levamisole, the gamma-amino butyric acid agonist piperazine, and the avermectins which open Cl- channels. The physiology and pharmacology of neuromuscular transmission in nematodes is reviewed and the actions of antinematodal drugs which interfere with the transmission described. The results of experiments on the large porcine-intestinal nematode parasite, Ascaris suum, form the basis of the account presented but experiments on other nematodes suggest that these observations may be generalized. Results of some experiments on the small free living nematode Caenorhabditis elegans are also included.

Jentsch TJ et al. (2018) Physiol Rev "CLC Chloride Channels and Transporters: Structure, Function, Physiology, and Disease."

Jentsch TJ, Pusch M

[Physiol Rev, 2018]

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 -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.

Yue X et al. (2019) Cell Mol Life Sci "Distinct functions of TMC channels: a comparative overview."

Yue X, Sheng Y, Kang L, Xiao R

[Cell Mol Life Sci, 2019]

In the past two decades, transmembrane channel-like (TMC) proteins have attracted a significant amount of research interest, because mutations of Tmc1 lead to hereditary deafness. As evolutionarily conserved membrane proteins, TMC proteins are widely involved in diverse sensorimotor functions of many species, such as hearing, chemosensation, egg laying, and food texture detection. Interestingly, recent structural and physiological studies suggest that TMC channels may share a similar membrane topology with the Ca²⁺-activated Cl^- channel TMEM16 and the mechanically activated OSCA1.2/TMEM63 channel. Namely, these channels form dimers and each subunit consists of ten transmembrane segments. Despite this important structural insight, a key question remains: what is the gating mechanism of TMC channels? The major technical hurdle to answer this question is that the reconstitution of TMC proteins as functional ion channels has been challenging in mammalian heterologous systems. Since TMC channels are conserved across taxa, genetic studies of TMC channels in model organisms such as C. elegans, Drosophila, and zebrafish may provide us critical information on the physiological function and regulation of TMCs. Here, we present a comparative overview on the diverse functions of TMC channels in different species.