CLIC1-mediated autophagy confers resistance to DDP in gastric cancer.

Gastric cancer has been a constant concern to researchers as one of the most common malignant tumors worldwide. The treatment options for gastric cancer include surgery, chemotherapy and traditional Chinese medicine. Chemotherapy is an effective treatment for patients with advanced gastric cancer. Cisplatin (DDP) has been approved as a critical chemotherapy drug to treat various kinds of solid tumors. Although DDP is an effective chemotherapeutic agent, many patients develop drug resistance during treatment, which has become a severe problem in clinical chemotherapy. This study aims to investigate the mechanism of DDP resistance in gastric cancer. The results show that intracellular chloride channel 1 (CLIC1) expression was increased in AGS/DDP and MKN28/DDP, and as compared to the parental cells, autophagy was activated. In addition, the sensitivity of gastric cancer cells to DDP was decreased compared to the control group, and autophagy increased after overexpression of CLIC1. On the contrary, gastric cancer cells were more sensitive to cisplatin after transfection of CLIC1siRNA or treatment with autophagy inhibitors. These experiments suggest that CLIC1 could alter the sensitivity of gastric cancer cells to DDP by activating autophagy. Overall, the results of this study recommend a novel mechanism of DDP resistance in gastric cancer.

Sodium Danshensu ameliorates cerebral ischemia/reperfusion injury by inhibiting CLIC4/NLRP3 inflammasome-mediated endothelial cell pyroptosis.

Endothelial pyroptosis promotes cerebral ischemia/reperfusion injury (CIRI). Sodium Danshensu (SDSS) has been shown to attenuate CIRI and have anti-inflammatory properties in endothelial cells. However, the mechanism and effect of SDSS on alleviating endothelial pyroptosis after CIRI remains poorly understood. Thus, we aimed to investigate the efficacy and mechanism of SDSS in reducing endothelial pyroptosis. It has been shown that SDSS administration inhibited NLRP3 inflammasome-mediated pyroptosis. As demonstrated by protein microarrays, molecular docking, CETSA and ITDRFCETSA , SDSS bound strongly to CLIC4. Furthermore, SDSS can decrease its expression and inhibit its translocation. Its effectiveness was lowered by CLIC4 overexpression but not by knockdown. Overall The beneficial effect of SDSS against CIRI in this study can be ascribed to blocking endothelial pyroptosis by binding to CLIC4 and then inhibiting chloride efflux-dependent NLRP3 inflammasome activation.

Targeting macrophagic PIM-1 alleviates osteoarthritis by inhibiting NLRP3 inflammasome activation via suppressing mitochondrial ROS/Cl- efflux signaling pathway.

BACKGROUND: Osteoarthritis (OA), in which macrophage-driven synovitis is considered closely related to cartilage destruction and could occur at any stage, is an inflammatory arthritis. However, there are no effective targets to cure the progression of OA. The NOD-, LRR-,and pyrin domain-containing protein 3 (NLRP3) inflammasome in synovial macrophages participates in the pathological inflammatory process and treatment strategies targeting it are considered to be an effective approach for OA. PIM-1 kinase, as a downstream effector of many cytokine signaling pathways, plays a pro-inflammatory role in inflammatory disease. METHODS: In this study, we evaluated the expression of the PIM-1 and the infiltration of synovial macrophages in the human OA synovium. The effects and mechanism of PIM-1 were investigated in mice and human macrophages stimulated by lipopolysaccharide (LPS) and different agonists such as nigericin, ATP, Monosodium urate (MSU), and Aluminum salt (Alum). The protective effects on chondrocytes were assessed by a modified co-culture system induced by macrophage condition medium (CM). The therapeutic effect in vivo was confirmed by the medial meniscus (DMM)-induced OA in mice. RESULTS: The expression of PIM-1 was increased in the human OA synovium which was accompanied by the infiltration of synovial macrophages. In vitro experiments, suppression of PIM-1 by SMI-4a, a specific inhibitor, rapidly inhibited the NLRP3 inflammasome activation in mice and human macrophages and gasdermin-D (GSDME)-mediated pyroptosis. Furthermore, PIM-1 inhibition specifically blocked the apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization in the assembly stage. Mechanistically, PIM-1 inhibition alleviated the mitochondrial reactive oxygen species (ROS)/chloride intracellular channel proteins (CLICs)-dependent Cl- efflux signaling pathway, which eventually resulted in the blockade of the ASC oligomerization and NLRP3 inflammasome activation. Furthermore, PIM-1 suppression showed chondroprotective effects in the modified co-culture system. Finally, SMI-4a significantly suppressed the expression of PIM-1 in the synovium and reduced the synovitis scores and the Osteoarthritis Research Society International (OARSI) score in the DMM-induced OA model. CONCLUSIONS: Therefore, PIM-1 represented a new class of promising targets as a treatment of OA to target these mechanisms in macrophages and widened the road to therapeutic strategies for OA.

Aerobic exercises regulate the epididymal anion homeostasis of high-fat diet-induced obese rats through TRPA1-mediated Cl- and HCO3- secretion†.

Aerobic exercises could improve the sperm motility of obese individuals. However, the underlying mechanism has not been fully elucidated, especially the possible involvement of the epididymis in which sperm acquire their fertilizing capacity. This study aims to investigate the benefit effect of aerobic exercises on the epididymal luminal milieu of obese rats. Sprague-Dawley male rats were fed on a normal or high-fat diet (HFD) for 10 weeks and then subjected to aerobic exercises for 12 weeks. We verified that TRPA1 was located in the epididymal epithelium. Notably, aerobic exercises reversed the downregulated TRPA1 in the epididymis of HFD-induced obese rats, thus improving sperm fertilizing capacity and Cl- concentration in epididymal milieu. Ussing chamber experiments showed that cinnamaldehyd (CIN), agonist of TRPA1, stimulated an increase of the short-circuit current (ISC) in rat cauda epididymal epithelium, which was subsequently abolished by removing the ambient Cl- and HCO3-. In vivo data revealed that aerobic exercises increased the CIN-stimulated Cl- secretion rate of epididymal epithelium in obese rats. Pharmacological experiments revealed that blocking cystic fibrosis transmembrane regulator (CFTR) and Ca2+-activated Cl- channel (CaCC) suppressed the CIN-stimulated anion secretion. Moreover, CIN application in rat cauda epididymal epithelial cells elevated intracellular Ca2+ level, and thus activate CACC. Interfering with the PGHS2-PGE2-EP2/EP4-cAMP pathway suppressed CFTR-mediated anion secretion. This study demonstrates that TRPA1 activation can stimulate anion secretion via CFTR and CaCC, which potentially forming an appropriate microenvironment essential for sperm maturation, and aerobic exercises can reverse the downregulation of TRPA1 in the epididymal epithelium of obese rats.

3D Biomimetic Calcified Cartilaginous Callus that Induces Type H Vessels Formation and Osteoclastogenesis.

The formation of a calcified cartilaginous callus (CACC) is crucial during bone repair. CACC can stimulate the invasion of type H vessels into the callus to couple angiogenesis and osteogenesis, induce osteoclastogenesis to resorb the calcified matrix, and promote osteoclast secretion of factors to enhance osteogenesis, ultimately achieving the replacement of cartilage with bone. In this study, a porous polycaprolactone/hydroxyapatite-iminodiacetic acid-deferoxamine (PCL/HA-SF-DFO) 3D biomimetic CACC is developed using 3D printing. The porous structure can mimic the pores formed by the matrix metalloproteinase degradation of the cartilaginous matrix, HA-containing PCL can mimic the calcified cartilaginous matrix, and SF anchors DFO onto HA for the slow release of DFO. The in vitro results show that the scaffold significantly enhances angiogenesis, promotes osteoclastogenesis and resorption by osteoclasts, and enhances the osteogenic differentiation of bone marrow stromal stem cells by promoting collagen triple helix repeat-containing 1 expression by osteoclasts. The in vivo results show that the scaffold significantly promotes type H vessels formation and the expression of coupling factors to promote osteogenesis, ultimately enhancing the regeneration of large-segment bone defects in rats and preventing dislodging of the internal fixation screw. In conclusion, the scaffold inspired by biological bone repair processes effectively promotes bone regeneration.

Trans-ε-viniferin as an inhibitor of TMEM16A preventing intestinal smooth muscle contraction.

TMEM16A regulator is an important tool to study the physiological functions and pathogenesis related to TMEM16A. In the present study, trans-ε-viniferin (TV) was identified as a TMEM16A inhibitor with inhibitory activity against TMEM16A mediated Cl- currents, which was reversible, without affecting intracytoplasmic Ca2+ concentration and TMEM16A protein expression. TV inhibited intestinal peristalsis and prolonged gastrointestinal transport time. TV could inhibit autonomic and Eact-stimulated intestinal contractility, and was equally effective in ACh- and HA-induced high contractile states. The results indicate that TV significantly inhibits the intestinal smooth muscle contraction, which may be applied in the treatment of TMEM16A-related intestinal dynamic abnormalities.

Hericium caput-medusae (Bull.:Fr.) Pers. fermentation concentrate polysaccharides improves intestinal bacteria by activating chloride channels and mucus secretion.

ETHNOPHARMACOLOGICAL RELEVANCE: As a traditional edible fungus in China and many other Asian countries, Hericium caput-medusae (Bull. Fr.) Pers. is widely used to improve the health of the gastrointestinal tract. For example, the drug "Weilexin Granules" is mainly composed of H. caput-medusae (Bull. Fr.) Pers. fermentation concentrate. However, the mechanism of action remains to be elucidated. AIMS OF THE STUDY: The purpose of this study was to assess whether polysaccharides from H. caput-medusae (Bull. Fr.) Pers. fermentation concentrate (HFP) exerts a gut protective effect and a regulatory effect on the intestinal microbiota through the chloride channels and mucus secretion. MATERIALS AND METHODS: HFP was extracted, characterized and different concentrations of HFP (100, 200, 400 mg/kg) were administered to mice for 14 days. The changes in gut microbiota were observed via 16S high throughput sequencing. Short-chain fatty acids (SCFAs) was detected by GC-MS. AB-PAS staining was used to observe the secretion of mucus. The chloride channel activity and protein expression were verified by short-circuit current measurement and Western blot. RESULTS: HFP regulated the abundance of gut microbiota in mice, with increased levels of Ruminococcaceae and Lachnospiraceae and reduced proportions of Staphylococcus and Enterobacter. HFP enhanced mucus volume as well as increased intestinal fluid secretion by activating the chloride channels. In addition, short-circuit current experiments also proved that HFP activates Cl⁻ currents targeting cystic fibrosis transmembrane conductance regulator (CFTR) and Anoamin1 (ANO1). CONCLUSION: In conclusion, HFP might increase intestinal fluid secretion by promoting Cl⁻ secretion, which in turn advanced mucus hydration as well as regulated gut microbiota to improve intestinal health. Therefore, H. caput-medusae (Bull. Fr.) Pers. could be potentially used in the regulation of intestinal secretion and microbes.

In vivo inhibition of epileptiform afterdischarges in rat hippocampus by light-activated chloride channel, stGtACR2.

AIMS: The blue light-sensitive chloride-conducting opsin, stGtACR2, provides potent optogenetic silencing of neurons. The present study investigated whether activation of stGtACR2 in granule cells of the dentate gyrus (DG) inhibits epileptic afterdischarges in a rat model. METHODS: Rats were bilaterally injected with 0.9 µl of AAV2/7-CaMKIIα-stGtACR2-fusionred in the DG. Three weeks later, afterdischarges were recorded from the DG by placing an optrode at the injection site and a stimulation electrode in the perforant path (PP). Afterdischarges were evoked every 10 min by unilateral electrical stimulation of the PP (20 Hz, 10 s). During every other afterdischarge, the DG was illuminated for 5 or 30 s, first ipsilaterally and then bilaterally to the PP stimulation. The line length metric of the afterdischarges was compared between illumination conditions. RESULTS: Ipsilateral stGtACR2 activation during afterdischarges decreased the local field potential line length only during illumination and specifically at the illuminated site but did not reduce afterdischarge duration. Bilateral illumination did not terminate the afterdischarges. CONCLUSION: Optogenetic inhibition of excitatory neurons using the blue-light sensitive chloride channel stGtACR2 reduced the amplitude of electrically induced afterdischarges in the DG at the site of illumination, but this local inhibitory effect was insufficient to reduce the duration of the afterdischarge.

High-salt diet accelerates bone loss accompanied by activation of ion channels related to kidney and bone tissue in ovariectomized rats.

Excessive salt intake can induce a variety of diseases, such as hypertension, cardiovascular disease, kidney disease and so on，it is also one of the factors promoting bone resorption. The mechanism of osteoporosis-induced exacerbations of high salt diet is not well-defined. In this study, we used ovariectomized 6-month-old Sprague Dawley rats to construct a high bone turnover model, and then administrated with high sodium chloride diet (2.0% w/w NaCl, 8.0% w/w NaCl) for 12 weeks to observe the effect of high salt diet on bone metabolism. The results showed that high salt diet could lead to the destruction of bone microstructure, promote the excretion of urinary calcium and phosphorus and accelerate the bone turnover, as well as cause the pathologic structural abnormalities in renal tubular. At the same time, it was accompanied by the up-regulated expression of the epithelial sodium channel (ENaCα), voltage-gated chloride channels (ClC)- 3 and the down-regulated expression of Na-Cl cotransporter (NCC), sodium calcium exchanger (NCX1) in femoral tissue and renal tubules. These findings confirm that high salt diet can destroy the microstructure of bone by increasing bone resorption and affect some ion channels of bone tissue and renal tubule in ovariectomized rats.

Improved growth and tuber quality of transgenic potato plants overexpressing either NHX antiporter, CLC chloride channel, or both.

The nutritional enhancement of potato plants (Solanum tuberosum L.,) is highly critical. As it is considered a worldwide basic vegetarian nutrition to maintain health. S. tuberosum is one of the foremost staples and the world's fourth-largest food crop. In advance, its need is increasing because of its high-industrial value and population blast. To improve both potato growth and behavior under harsh environmental conditions, we produced transgenic potato plants overexpressing either VvNHX (a sodium proton antiporter from Vitis vinifera), VvCLC (a chloride channel from Vitis vinifera), or both. Control and transgenic plants were grown in greenhouse and field under non-stressed conditions for 85 days in order to characterize their phenotype and evaluate their agronomical performance. To this aim, the evaluation of plant growth parameters, tuber yields and characteristics (calibers, eye number and color), the chemical composition of tubers, was conducted and compared between the different lines. The obtained results showed that transgenic plants displayed an improved growth (flowering precocity, gain of vigor and better vegetative growth) along with enhanced tuber yields and quality (increased protein and starch contents). Our findings provide then insight into the role played by the VvNHX antiport and the VvCLC channel and a greater understanding of the effect of their overexpression in potato plants.

Rifaximin and lubiprostone mitigate liver fibrosis development by repairing gut barrier function in diet-induced rat steatohepatitis.

BACKGROUND: Although gut-derived lipopolysaccharide (LPS) affects the progression of non-alcoholic steatohepatitis (NASH) pathogenesis, few studies have focused on this relationship to develop treatments for NASH. AIMS: To explore the effects of combination with rifaximin and lubiprostone on NASH liver fibrosis through the modulation of gut barrier function. METHODS: To induce steatohepatitis, F344 rats were fed a choline-deficient l-amino acid-defined (CDAA) diet for 12 weeks and received oral administration of rifaximin and/or lubiprostone. Histological, molecular, and fecal microbial analyses were performed. Barrier function in Caco-2 cells were assessed by in vitro assays. RESULTS: Combination rifaximin/lubiprostone treatment significantly suppressed macrophage expansion, proinflammatory responses, and liver fibrosis in CDAA-fed rats by blocking hepatic translocation of LPS and activation of toll-like receptor 4 signaling. Rifaximin and lubiprostone improved intestinal permeability via restoring tight junction proteins (TJPs) with the intestinal activation of pregnane X receptor and chloride channel-2, respectively. Moreover, this combination increased the abundance of Bacteroides, Lactobacillus, and Faecalibacterium as well as decreased that of Veillonella resulting in an increase of fecal short-chain fatty acids and a decrease of intestinal sialidase activity. Both agents also directly suppressed the LPS-induced barrier dysfunction and depletion of TJPs in Caco-2 cells. CONCLUSION: The combination of rifaximin and lubiprostone may provide a novel strategy for treating NASH-related fibrosis.

Role of ANO1 in tumors and tumor immunity.

Dysregulation of gene amplification, cell-signaling-pathway transduction, epigenetic and transcriptional regulation, and protein interactions drives tumor-cell proliferation and invasion, while ion channels also play an important role in the generation and development of tumor cells. Overexpression of Ca2+-activated Cl- channel anoctamin 1 (ANO1) is shown in numerous cancer types and correlates with poor prognosis. However, the mechanisms involved in ANO1-mediated malignant cellular transformation and the role of ANO1 in tumor immunity remain unknown. In this review, we discuss recent studies to determine the role of ANO1 in tumorigenesis and provide novel insights into the role of ANO1 in the context of tumor immunity. Furthermore, we analyze the roles and potential mechanisms of ANO1 in different types of cancers, and provide novel notions for the role of ANO1 in the tumor microenvironment and for potential use of ANO1 in clinical applications. Our review shows that ANO1 is involved in tumor immunity and microenvironment, and may, therefore, be an effective biomarker and therapeutic drug target.

Properties of synchronous spontaneous Ca2+ transients in the mural cells of rat rectal arterioles.

Synchrony of spontaneous Ca2+ transients among venular mural cells (smooth muscle cells and pericytes) in visceral organs relies on the intercellular spread of L-type voltage-dependent Ca2+ channel (LVDCC)-dependent depolarisations. However, the mechanisms underlying the synchrony of spontaneous Ca2+ transients between arteriolar mural cells are less understood. The spontaneous intracellular Ca2+ dynamics of arteriolar mural cells in the rat rectal submucosa were visualised by Cal-520 Ca2+ imaging to analyse their synchrony. The mural cells in fine arterioles that had a rounded cell body with several extended processes developed spontaneous 'synchronous' Ca2+ transients arising from Ca2+ released from sarcoendoplasmic reticulum Ca2+ stores. Gap junction blockers (3 µM carbenoxolone, 10 µM 18ß-glycyrrhetinic acid), a Ca2+-activated Cl- channel (CaCC) blocker (100 µM 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid) or lowering extracellular Cl- concentration (from 134.4 to 12.4 mM) disrupted the synchrony of Ca2+ transients between arteriolar mural cells. Blockers of T-type voltage-dependent Ca2+ channels (TVDCCs, 1 µM mibefradil or ML218) or LVDCCs (1 µM nifedipine) reduced the Ca2+ transient frequency or their area under curve (AUC), respectively. However, neither TVDCC nor LVDCC blockers disrupted the synchrony of Ca2+ transients among arteriolar mural cells. This is in contrast with rectal venules in which nifedipine disrupted the synchrony of spontaneous Ca2+ transients. Thus, spontaneous transient depolarisations arising from the opening of CaCCs may effectively spread to neighbouring arteriolar mural cells via gap junctions to maintain the Ca2+ transient synchrony. Activation of TVDCCs appears to accelerate spontaneous Ca2+ transients, while LVDCCs predominantly contribute to the duration of Ca2+ transients.

Pharmacological characterization of histamine-gated chloride channels from the housefly Musca domestica.

The biogenic amine histamine (HA) is not only the neurotransmitter of photoreceptors but also has important roles in mechanosensory reception, temperature preference, sleep and olfactory processing in insects. Two cDNAs (MdhclA and MdhclB) that encode HA-gated chloride channel subunits (MdHCLA and MdHCLB) were cloned from the housefly Musca domestica. The cRNAs were injected into Xenopus laevis oocytes to examine the functions and pharmacological characteristics of MdHCLA and MdHCLB channels using a two-electrode voltage clamp method. HA was used to activate MdHCLA and MdHCLB channels to evoke inward currents with EC50s of 33.1µM and 6.28µM, respectively. 2-(3-Trifluoromethylphenyl)histamine, an HA H1 receptor agonist, was a partial agonist of MdHCLB receptors with an EC50 of 49.4µM. MdHCLB channels were also activated by γ-aminobutyric acid (GABA) and monoamines, such as octopamine, serotonin (5-HT) and dopamine (DA); 5-HT and DA also acted as competitive antagonists. GABA acted as a full agonist of MdHCLB receptors with an EC50 of 1.11mM. d-Tubocurarine, cimetidine and picrotoxinin were poor inhibitors of HA- and GABA-evoked currents in MdHCLB channels. Our data show that HCLB channels are more sensitive to agonists when compared with HCLA channels. HCLB channels are also affected by antagonists but insusceptible to known insecticides that target GABA- and glutamate-gated chloride channels.

Secreted CLCA1 modulates TMEM16A to activate Ca(2+)-dependent chloride currents in human cells.

Calcium-activated chloride channel regulator 1 (CLCA1) activates calcium-dependent chloride currents; neither the target, nor mechanism, is known. We demonstrate that secreted CLCA1 activates calcium-dependent chloride currents in HEK293T cells in a paracrine fashion, and endogenous TMEM16A/Anoctamin1 conducts the currents. Exposure to exogenous CLCA1 increases cell surface levels of TMEM16A and cellular binding experiments indicate CLCA1 engages TMEM16A on the surface of these cells. Altogether, our data suggest that CLCA1 stabilizes TMEM16A on the cell surface, thus increasing surface expression, which results in increased calcium-dependent chloride currents. Our results identify the first Cl(-) channel target of the CLCA family of proteins and establish CLCA1 as the first secreted direct modifier of TMEM16A activity, delineating a unique mechanism to increase currents. These results suggest cooperative roles for CLCA and TMEM16 proteins in influencing the physiology of multiple tissues, and the pathology of multiple diseases, including asthma, COPD, cystic fibrosis, and certain cancers.

Regulation of the membrane insertion and conductance activity of the metamorphic chloride intracellular channel protein CLIC1 by cholesterol.

The Chloride Intracellular ion channel protein CLIC1 has the ability to spontaneously insert into lipid membranes from a soluble, globular state. The precise mechanism of how this occurs and what regulates this insertion is still largely unknown, although factors such as pH and redox environment are known contributors. In the current study, we demonstrate that the presence and concentration of cholesterol in the membrane regulates the spontaneous insertion of CLIC1 into the membrane as well as its ion channel activity. The study employed pressure versus area change measurements of Langmuir lipid monolayer films; and impedance spectroscopy measurements using tethered bilayer membranes to monitor membrane conductance during and following the addition of CLIC1 protein. The observed cholesterol dependent behaviour of CLIC1 is highly reminiscent of the cholesterol-dependent-cytolysin family of bacterial pore-forming proteins, suggesting common regulatory mechanisms for spontaneous protein insertion into the membrane bilayer.

Synthetic chloride channel regulates cell membrane potentials and voltage-gated calcium channels.

Synthetic ion channels are of great interest in mimicking the biological functions of natural ion channels. Although many synthetic ion channels could selectively mediate ion transport across lipid bilayer membranes, the biological roles played by these synthetic channels in living systems remain essentially obscure. In this study, we report the application of a synthetic chloride (Cl(-)) channel as a powerful tool to perturb and regulate a series of biological processes related or coupled to the changes of cell membrane potentials. This is the first example in which an artificial ion channel can regulate natural voltage-gated calcium channels, intracellular calcium concentrations, and the contraction of smooth muscle cells via modulating cell membrane potentials in living cells and tissues. The present study on the ability of the synthetic chloride channel to perturb functions of natural ion channels may open new perspectives for the applications of other synthetic ion channels in biological systems.

Imaging the electric field associated with mouse and human skin wounds.

We have developed a noninvasive instrument called the bioelectric field imager (BFI) for mapping the electric field between the epidermis and the stratum corneum near wounds in both mouse and human skin. Rather than touching the skin, the BFI vibrates a small metal probe with a displacement of 180 mum in air above the skin to detect the surface potential of the epidermis through capacitative coupling. Here we describe our first application of the BFI measuring the electric field between the stratum corneum and epidermis at the margin of skin wounds in mice. We measured an electric field of 177+/-14 (61) mV/mm immediately upon wounding and the field lines pointed away from the wound in all directions around it. Because the wound current flows immediately upon wounding, this is the first signal indicating skin damage. This electric field is generated at the outer surface of the epidermis by the outward flow of the current of injury. An equal and opposite current must flow within the multilayered epidermis to generate an intraepidermal field with the negative pole at the wound site. Because the current flowing within the multilayered epidermis is spread over a larger area, the current density and subsequent E field generated in that region is expected to be smaller than that measured by the BFI beneath the stratum corneum. The field beneath the stratum corneum typically remained in the 150-200 mV/mm range for 3 days and then began to decline over the next few days, falling to zero once wound healing was complete. The mean wound field strength decreased by 64+/-7% following the application of the sodium channel blocker, amiloride, to the skin near the wound and increased by 82+/-21% following the application of the Cl- channel activator, prostaglandin E2.

A synthetic, chloride-selective channel that alters chloride transport in epithelial cells.

An Ussing chamber was used to demonstrate that synthetic amphiphilic anion transporters function as chloride transporters in mammalian airway epithelial cells.

The avermectin receptors of Haemonchus contortus and Caenorhabditis elegans.

Most of the recent evidence suggests that the avermectin/milbemycin family of anthelmintics act via specific interactions with glutamate-gated chloride channels. These channels are encoded by a small family of genes in nematodes, though the composition of the gene family and the function of the individual members of the family may vary between species. We review our current knowledge concerning the properties of the glutamate-gated chloride channels from Caenorhabditis elegans and the related parasite, Haemonchus contortus. We conclude that the biological effects of the avermectins/milbemycins can be largely explained by the known pharmacology and distribution of the glutamate-gated chloride channels and that differences between the glutamate-gated chloride channels from different nematodes may underlie species-specific variations in anthelmintic action.