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Chloride Transport across the Lysosomal Membrane
Published in Bruno Gasnier, Michael X. Zhu, Ion and Molecule Transport in Lysosomes, 2020
Sonali Saha, Anja Blessing, Thomas J. Jentsch
In endosomes, electrogenic transport of chloride into the lumen was shown to be essential for acidification (Günther et al., 2003; Hara-Chikuma et al., 2005; Novarino et al., 2010; Van Dyke, 1993). Similarly, chloride flux across lysosomal membranes was proposed to enable luminal acidification of isolated lysosomes (Dell’Antone, 1979; Ohkuma et al., 1982). Since Clˉ/H+-antiporters of the CLC family of Clˉ-channels and Clˉ-transporters (Jentsch, 2015; Jentsch and Pusch, 2018), in particular ClC-5 (Günther et al., 2003; Novarino et al., 2010; Piwon et al., 2000) and ClC-3 (Hara-Chikuma et al., 2005), facilitated endosomal acidification, the lysosome-residing member of this family ClC-7, together with its ß-subunit Ostm1 (Kasper et al., 2005; Kornak et al., 2001; Lange et al., 2006), was supposed to mediate the same process in lysosomes (Kornak et al., 2001). However, using ratiometric fluorescence measurements, we did not detect differences in lysosomal pH between cells derived from WT and ClC-7 knockout mice (Kasper et al., 2005; Lange et al., 2006; Steinberg et al., 2010; Weinert et al., 2010).
Lysosomal Ion Channels and Human Diseases
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Peng Huang, Mengnan Xu, Yi Wu, Xian-Ping Dong
Endosomes and lysosomes are highly enriched in Cl− that may control their trafficking and degradative functions (Chakraborty et al., 2017; Jentsch and Pusch, 2018; Saha et al., 2015; Xu and Ren, 2015). A subgroup of ClC proteins (ClC3 through ClC7, encoded by CLCN3–7 genes) resides in the intracellular membranes of the endolysosomal pathway. Due to their intracellular localization, biophysical characterization of the intracellular ClCs only becomes possible when they are heterologously expressed in the PM. All these channels in the PM yield outwardly rectifying anion currents [ClC3 (Guzman et al., 2015; Li et al., 2002), ClC4 (Friedrich et al., 1999; Mohammad-Panah et al., 2003), ClC5 (Friedrich et al., 1999; Steinmeyer et al., 1995), ClC6 (Buyse et al., 1997; Neagoe et al., 2010), and ClC7 (Leisle et al., 2011)] that are inhibited by low extracellular pH (Friedrich et al., 1999; Leisle et al., 2011). However, the electrophysiological properties and physiological roles of endolysosomal ClCs are far from being understood. They were initially believed to be Cl− channels like the other four mammalian ClC channels in the PM (i.e. ClC1, ClC2, ClCKa, and ClCKb). However, later studies suggest that ClC3-ClC7 are coupled 2Cl−/1H+ antiporters with an anion conductance sequence of Cl− > Br− > I− (Chadda et al., 2016; Graves et al., 2008; Jentsch and Pusch, 2018; Leisle et al., 2011; Picollo and Pusch, 2005; Scheel et al., 2005; Weinert et al., 2010). They all have a conserved ‘gating glutamate’ that participate in coupling H+ to Cl− transport. Neutralization of the ‘gating glutamate’ results in uncoupled Cl− passive conductance and eliminates voltage dependence (Jentsch and Pusch, 2018; Leisle et al., 2011; Novarino 2010; Picollo and Pusch, 2005; Scheel et al., 2005). Endolysosomal ClC proteins form homo- or heteromeric dimers, in which each monomer contains an ion conductance pathway. The physiological roles of endolysosomal ClCs are believed to provide countercurrents to allow efficient endolysosomal acidification by the V-ATPase (Jentsch and Pusch, 2018).
Reconstituted Membrane Systems for Assaying Membrane Proteins in Controlled Lipid Environments
Published in Qiu-Xing Jiang, New Techniques for Studying Biomembranes, 2020
Proteoliposomes may contain enriched membrane proteins in either native or artificial membranes. Microsomes prepared from ER membranes have been extensively used for studying in vitro translation and co-translational translocation of proteins (e.g.,10,11). In intact cells, flux of fluorophores through native biomembranes or isolated organelles, such as mitochondria or microsomes, could be directly employed to study the functionality of membranes proteins, especially transporters.12–14 The most commonly applied systems are cells expressing endogenous transporters or immortalized cells from the same tissues that over-express target membranes proteins. This method has advantages of containing native proteins in cell membranes and possibly their interacting partners which might be important for their function. In the latter case, the secondary cultures may still have lipid environments that are different from the primary cells from the original tissues. On the other hand, transient or stable over-expression systems such as X. leavis Oocytes or tumor cell lines have the advantage of producing a large quantity of the proteins of interest. The intact expression system allows identification and characterization of a large number of membrane systems from plasma and/or intracellular membranes. However, the complexity of the secondary expression systems is associated with the interference from homologous or contaminant proteins, which could give rise to false positive results. The application of specific inhibitors is important in these systems to separate the activities of the target molecules. But for intracellular proteins in intact membrane systems, inaccessibility of inhibitor-binding sites may limit the efficacy of specific inhibitors in reaching the targeted membrane proteins. Further, incomplete separation of different intracellular membranes and plasma membranes in cellular fractionation usually makes it difficult to achieve a high level of certainty in localizing the protein function to the right compartments. Genetic manipulation and high-resolution electron microscopy are usually required. In general, the above-mentioned limitations have introduced uncertainty or sometimes caused controversies into varying aspects of investigating the structure, function and regulation of specific membrane proteins. For example, clc-3 Cl−/H+ exchanger was proposed by some to be present in insulin-secretory granules,15 which was refuted by others based on antibody specificity.16
ILK enhances migration and invasion abilities of human endometrial stromal cells by facilitating the epithelial–mesenchymal transition
Published in Gynecological Endocrinology, 2018
Qiao-Mei Zheng, Xiao-Yun Chen, Qiu-Fang Bao, Jin Yu, Li-Hong Chen
Although the underlying pathogenesis of the ESCs survived elsewhere and developed into endometriosis remains poorly understood, higher cell migration and invasion abilities have been reported to be associated with endometriosis disease progression. HIF-1α was involved in the pathogenesis of endometriosis by promoting ESCs migration and invasion [18]. PRL-3 facilitated the pathogenesis of endometriosis by promoting migration and invasion abilities of ESCs [19]. CAPN-7 also promoted endometriosis by facilitating the migration and invasion of ESCs [20]. ClC-3 expression level was well-correlated to the clinical characteristics and symptoms of endometriosis patients via increasing the migration and invasion abilities of cells from patients with endometriosis [21]. In our previous study, we identified that Periostin facilitated the migration, invasion abilites of ESCs by ILK pathway [17]. Furthermore, our present study identified higher migration and invasion abilities of ESCs of endometriosis.
The slow light and dark oscillation of the clinical electro‐oculogram
Published in Clinical and Experimental Optometry, 2018
The second chloride channel identified is a calcium‐dependent chloride channel that is expressed in the basal membrane of canine retinal pigment epithelium and is believed to regulate indirectly chloride currents.2003 However, no similar channel has been identified in human retinal pigment epithelium to date. The ClC‐3 and ClC‐5 channels were expressed strongly at the apical membrane and would suggest a limited role in altering basolateral chloride conductance by these channels.2002 However, CIC‐2 immunohistochemistry revealed weak expression in human adult retinal pigment epithelium cells2002 despite messenger and protein expression. CIC‐2 is expressed in foetal retinal pigment epithelium2000 and is associated with retinal degeneration in knockout mouse models.2001 Hartzell and Qu2003 reported a CIC‐2 type current in Xenopus retinal pigment epithelium in which the inward current increased in response to a fall in extracellular pH.