CLH-3, a ClC-2 anion channel ortholog activated during meiotic maturation in C. elegans oocytes

Rutledge, Eric; Bianchi, Laura; Christensen, Michael J.; Boehmer, Christoph; Morrison, Rebecca; Broslat, Adam; Beld, Andrew M.; George, Alfred L.; Greenstein, David; Strange, Kevin

doi:10.1016/s0960-9822(01)00051-3

Cited by 64 publications

(141 citation statements)

References 30 publications

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“…1). Interestingly, a Caenorhabditis elegans homolog of ClC-2, termed CLH-3, has recently been characterized (44). Although CLH-3 can be activated by cell swelling, the physiological trigger for activation is the induction of oocyte meiotic maturation.…”

Section: Discussionmentioning

confidence: 99%

Loss of Hyperpolarization-activated Cl− Current in Salivary Acinar Cells from Clcn2 Knockout Mice

Nehrke

Arreola

Nguyen

et al. 2002

Journal of Biological Chemistry

107

105

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ClC-2 is localized to the apical membranes of secretory epithelia where it has been hypothesized to play a role in fluid secretion. Although ClC-2 is clearly the inwardly rectifying anion channel in several tissues, the molecular identity of the hyperpolarization-activated Cl ؊ current in other organs, including the salivary gland, is currently unknown. To determine the nature of the hyperpolarization-activated Cl ؊ current and to examine the role of ClC-2 in salivary gland function, a mouse line containing a targeted disruption of the Clcn2 gene was generated. The resulting homozygous Clcn2 ؊/؊ mice lacked detectable hyperpolarization-activated chloride currents in parotid acinar cells and, as described previously, displayed postnatal degeneration of the retina and testis. The magnitude and biophysical characteristics of the volume-and calcium-activated chloride currents in these cells were unaffected by the absence of ClC-2. Although ClC-2 appears to contribute to fluid secretion in some cell types, both the initial and sustained salivary flow rates were normal in Clcn2 ؊/؊ mice following in vivo stimulation with pilocarpine, a cholinergic agonist. In addition, the electrolytes and protein contents of the mature secretions were normal. Because ClC-2 has been postulated to contribute to cell volume control, we also examined regulatory volume decrease following cell swelling. However, parotid acinar cells from Clcn2 ؊/؊ mice recovered volume with similar efficiency to wild-type littermates. These data demonstrate that ClC-2 is the hyperpolarization-activated Cl ؊ channel in salivary acinar cells but is not essential for maximum chloride flux during stimulated secretion of saliva or acinar cell volume regulation.

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Section: Discussionmentioning

confidence: 99%

Loss of Hyperpolarization-activated Cl− Current in Salivary Acinar Cells from Clcn2 Knockout Mice

Nehrke

Arreola

Nguyen

et al. 2002

Journal of Biological Chemistry

107

105

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“…The channel is activated by meiotic cell-cycle progression and cell swelling (36). Channel activation requires dephosphorylation of two C-terminus serine residues, S742 and S747, by type 1 protein phosphatases.…”

Section: Introductionmentioning

confidence: 99%

Role of CBS and Bateman Domains in Phosphorylation-Dependent Regulation of a CLC Anion Channel

Yamada

Krzeminski

Bozóky

et al. 2016

Biophysical Journal

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Eukaryotic CLC anion channels and transporters are homodimeric proteins composed of multiple a-helical membrane domains and large cytoplasmic C-termini containing two cystathionine-b-synthase domains (CBS1 and CBS2) that dimerize to form a Bateman domain. The Bateman domains of adjacent CLC subunits interact to form a Bateman domain dimer. The functions of CLC CBS and Bateman domains are poorly understood. We utilized the Caenorhabditis elegans CLC-1/2/Ka/ Kb anion channel homolog CLH-3b to characterize the regulatory roles of CLC cytoplasmic domains. CLH-3b activity is reduced by phosphorylation or deletion of a 14-amino-acid activation domain (AD) located on the linker connecting CBS1 and CBS2. We demonstrate here that phosphorylation-dependent reductions in channel activity require an intact Bateman domain dimer and concomitant phosphorylation or deletion of both ADs. Regulation of a CLH-3b AD deletion mutant is reconstituted by intracellular perfusion with recombinant 14-amino-acid AD peptides. The sulfhydryl reactive reagent 2-(trimethylammonium)ethyl methanethiosulfonate bromide (MTSET) alters in a phosphorylation-dependent manner the activity of channels containing single cysteine residues that are engineered into the short intracellular loop connecting membrane a-helices H and I (H-I loop), the AD, CBS1, and CBS2. In contrast, MTSET has no effect on channels in which cysteine residues are engineered into intracellular regions that are dispensable for regulation. These studies together with our previous work suggest that binding and unbinding of the AD to the Bateman domain dimer induces conformational changes that are transduced to channel membrane domains via the H-I loop. Our findings provide new, to our knowledge, insights into the roles of CLC Bateman domains and the structurefunction relationships that govern the regulation of CLC protein activity by diverse ligands and signaling pathways.

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“…For example, a chloride conductance path with the above biophysical properties was detected in studies of salivary gland cells obtained from normal mice whereas this function was absent in salivary gland cells obtained from ClC-2 knock-out mice (4). Similarly, depletion of the Caenorhabditis elegans ortholog of ClC-2, CLH-3, in maturing oocytes by RNA interference leads to the complete abrogation of the native, inwardly rectifying chloride conductance (5).…”

mentioning

confidence: 99%

“…The physiological consequences of disrupting ClC-2 expression in these organisms implicate a role for this channel at the cell surface in modifying extracellular microenvironments or cell-cell communication (5,6). For example, ClC-2-deficient mice are blind, and the males are infertile.…”

mentioning

confidence: 99%

Evidence for a Functional Interaction between the ClC-2 Chloride Channel and the Retrograde Motor Dynein Complex

Dhani

Mohammad-Panah

Ahmed

et al. 2003

Journal of Biological Chemistry

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CLH-3, a ClC-2 anion channel ortholog activated during meiotic maturation in C. elegans oocytes

Cited by 64 publications

References 30 publications

Loss of Hyperpolarization-activated Cl− Current in Salivary Acinar Cells from Clcn2 Knockout Mice

Loss of Hyperpolarization-activated Cl− Current in Salivary Acinar Cells from Clcn2 Knockout Mice

Role of CBS and Bateman Domains in Phosphorylation-Dependent Regulation of a CLC Anion Channel

Evidence for a Functional Interaction between the ClC-2 Chloride Channel and the Retrograde Motor Dynein Complex

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