PubMed · 11907549
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Roderick MacKinnon. 2002-03-21. Nothing automatic about ion-channel structures.. https://doi.org/10.1038/416261b
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Endolysosomal abnormalities are particularly detrimental to the nervous system and have been implicated in neuropsychiatric disorders. Key regulators of the lysosomal and endosomal luminal ion homeostasis are CLC chloride/proton exchangers. We report 15 individuals carrying variants in CLCN3, encoding a ubiquitous endosomal 2Cl-/H+ exchanger, and provide updated clinical information for 5 previously reported individuals. Subjects displayed a broad spectrum of neuropsychiatric symptoms, including developmental delay, intellectual disability, and epilepsy. To reveal the pathogenic mechanism, we investigated ClC-3 variants-mediated ion transport and its regulation by the recently discovered inhibitory beta subunit TMEM9. 12/20 missense variants exhibited altered properties and fell into two classes: those affecting the region binding inhibitory TMEM9 carboxy-termini, and those that broaden the voltage range over which ClC-3 conducts ions. Surprisingly, the latter variants also attenuated TMEM9-mediated inhibition. Both classes produced a toxic gain-of-function, as evident from endolysosomal vacuolization by mutant ClC-3/TMEM9 overexpression. Our results expand the genetic and clinical spectrum of CLCN3-related disease, provide a solid basis for genetic counseling, and uncover an unexpected link between gating-associated conformational changes and inhibition by TMEM9.
This study aimed to evaluate the potential causal effect of chloride intracellular channel protein 5 (CLIC5) on the risk of chronic periodontitis (CP) using a Mendelian randomization (MR) approach. MR analysis was conducted utilizing publicly available summary statistics from genome-wide association studies summary statistics for CLIC5 and CP. Multiple MR methods, including inverse variance weighted, MR Egger, weighted median and weighted mode, were employed to estimate the causal effects. Sensitivity analyses, comprising leave-one-out and heterogeneity assessments were performed to evaluate the robustness of our findings. This MR analysis consistently revealed a negative association between CLIC5 and CP, with statistical significance achieved using the inverse variance weighted and weighted median methods. The concordant effect estimates obtained from all methodological approaches collectively indicated a potential protective effect of CLIC5 against CP. The sensitivity analyses further confirmed the robustness of these findings. This study provides genetic evidence suggesting a potential causal association between increased CLIC5 levels and decreased risk of CP. These findings augment the existing literature implicating chloride channel proteins in modulating the inflammatory processes pertinent to periodontal health. Further investigation is warranted to decipher the underlying biological mechanisms and to explore the potential of CLIC5 as a therapeutic target for CP.
Isoprostanes are liberated when reactive oxygen species (ROS) mediate the peroxidation of arachidonic acid or other polyunsaturated fatty acids. Because exposure to ROS is associated with tissue damage in the lung, we examined whether exposure to isoprostanes elicited a response in airway epithelial cells, potentially implicating isoprostane production in the epithelial response to oxidant stress. Application of the isoprostane 8-iso-prostaglandin E2 (8-iso-PGE2) produced an increase in transepithelial anion secretion across monolayers of the human airway epithelial cell line Calu-3, measured as an increase in short circuit current (Isc). This increase in Isc was greater when 8-iso-PGE2 was applied to the basolateral rather than the apical face of the Calu-3 monolayers and was almost entirely abolished by the addition of diphenylamine-2-carboxylate, implicating the cystic fibrosis transmembrane conductance regulator Cl- channel in the response. Experiments with electrically isolated apical and basolateral membrane preparations revealed that 8-iso-PGE2 stimulated both apical Cl- and basolateral K+ conductances. Using reverse transcription-polymerase chain reaction, we found that Calu-3 cells express the TPalpha, but not the TPbeta, isoform of the receptor, and that these cells secrete in response to the thromboxane A2 (TP) receptor agonist 9,11-dideoxy-9alpha,11alpha-methanoepoxy-prostaglandin F2alpha (U-46619). However, although part of the response seems to mediated via TP receptors, there are significant non-TP receptor-mediated effects on both the apical and basolateral membranes of Calu-3 cells. This is the first report of an isoprostane eliciting an effect in airway epithelial cells and suggests a potential role for this class of molecules in pulmonary host defense.