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Ion Channels in Immune Cells
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Devasena Ponnalagu, Shridhar Sanghvi, Shyam S. Bansal, Harpreet Singh
Although chloride channels are important for cell-volume regulation, unfortunately they are often neglected due to their lack of molecular identity and nonselective nature. However, few of the plasma membrane anion channels characterized, such as ClSwell, GABAA, and CFTR, have been implicated in immune cell activation and function12,107–115. The role of chloride channels in the volume regulation of T cells was identified in pioneering research done in the 1980s21. They were defined as VRAC or ClSwell, as the permeability to anions increased in the peripheral blood mononuclear cells (PBMC) upon osmolarity changes. Later, LRRC8A was identified as a molecular component of ClSwell110. It is predicted to be a hexameric channel with a pannexin-like transmembrane topology comprising hetero multimers of LRRC8A and other LRRC8 (-B, -C, -D, and -E) subunits12. Interestingly, a case study demonstrated that a mutation in LRRC8 was responsible for agammaglobulinemia, a congenital syndrome defined by a defect in B cell development116. In patients with agammaglobulinemia, translocation of the LRRC8 gene was observed that led to the truncation of half of the seventh and complete deletion of the eighth and ninth LRR domains located at the C-terminal of the LRRC8 protein, which eventually resulted in the inhibition of B cell development and proliferation116. Furthermore, knockdown of the LRRC8 gene abolished hypotonicity-induced volume regulation in T cells, decreased their proliferation, and induced apoptosis12. Similar to neurons, activation of GABAA receptors in T cells has an inhibitory role. GABA inhibited T cell proliferation and production of IL-2 and IFN-γ in in vitro experiments. A possible mechanism that was proposed is that opening of GABAA receptor channels induces Cl− efflux, cell depolarization, and decreased Ca2+ influx, resulting in inhibition of T cell function12. In patients with cystic fibrosis as well, defects in the CFTR gene were suggested to contribute to the impaired immune response, thus strengthening the role of chloride channels in immune response12.
Emerging technologies in pediatrics: the paradigm of neonatal diabetes mellitus
Published in Critical Reviews in Clinical Laboratory Sciences, 2020
Nicolas C. Nicolaides, Christina Kanaka-Gantenbein, Nektaria Papadopoulou-Marketou, Amalia Sertedaki, George P. Chrousos, Ioannis Papassotiriou
Insulin is produced and secreted by the β-cells within the islets of Langerhans in the pancreas. At the cellular and molecular level, glucose enters the β-cell through its cognate transporter, the glucose transporter 2 (GLUT2) (Figure 1) [9,10]. In the cytoplasm, glucokinase converts enzymatically glucose to glucose-6-phosphate, which is then utilized by the metabolic pathway of glycolysis to generate adenosine triphosphate (ATP), thereby altering the ratio of ATP:ADP (adenosine diphosphate) [8]. This increased production of energy results in the closure of the ATP-sensitive potassium channels (KATP) and the subsequent generation of a membrane potential that triggers the activation of L-type voltage-gated calcium channels. As a result, calcium imported in the β-cell stimulates insulin-stored granules to secrete insulin through exocytosis (Figure 1) [8]. Interestingly, a recently identified subunit of volume-regulated anion channels (VRAC), known as leucine-rich repeat-containing protein 8 A (LRRC8A), was found to enhance the ability of beta-cells to sense glucose as well as to increase insulin secretion [11].
Mechanisms of octanoic acid potentiation of insulin secretion in isolated islets
Published in Islets, 2019
Tingting Zhang, Pan Chen, Charles A. Stanley, Toshinori Hoshi, Changhong Li
Electrophysiological studies of rat β-cells have demonstrated that Cl− currents are important for glucose-induced electrical activity.28,29 VSAC is a key component of β-cell intracellular Cl− homeostasis and plays an important role in regulation of insulin secretion.28,30,31 DCPIB, an inhibitor of VSACs, strongly and dose-dependently inhibits glucose- and tolbutamide-induced electrical currents in rat β-cells,33,34,38 similar to the results of our [Ca2+]i measurements in Sur1-/- mouse islets. DCPIB also inhibits GSIS in isolated rat islets, supporting that VSAC plays a critical role in insulin secretion.38 Thus the reported sensitivity of the insulin secretion process to DCPIB suggests that VSACs are a key component in insulin secretion. However, it must be reminded that DCPIB not only inhibits VSACs but also blocks glutamate transporters in glial cells.34 The potential contributions of DCPIB on targets other than VSACs are difficult to assess. Despite of the limitation of DCPIB, the VSAC mechanism is a plausible explanation of the OA effect on insulin secretion. SWELL1, encoded by LRRC8a, is an essential component of the VSAC39 and involved in regulation of cell volume and insulin secretion.30,39 We have found that the expression of LRRC8a in β-cells isolated from patients with loss-of-function mutations of KATP channels after pancreatectomy is increased about 9-fold in comparison to age-matched controls;40 this observation suggests that VSACs might be involved in dysregulation of insulin secretion in islets without functional KATP.
Identification of differentially expressed and methylated genes associated with rheumatoid arthritis based on network
Published in Autoimmunity, 2020
Di Zhang, ZhaoFang Li, RongQiang Zhang, XiaoLi Yang, DanDan Zhang, Qiang Li, Chen Wang, Xuena Yang, YongMin Xiong
LRRC8D is part of the leucine-rich repeat family of proteins, which is comprised of five members: LRRC8A, LRRC8B, LRRC8C, LRRC8D and LRRC8E. A genome-wide association study of rheumatoid arthritis study found that LRRC8D gene was associated with RA which using the stochastic search variable selection (SSVS) and the least absolute shrinkage and selection operator (LASSO) model selection algorithms [52]. Stuhlmann T reported that neurotransmitter-permeable LRRC8D-containing VRACs might have additional roles in autocrine/paracrine signalling within islets [53].