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These findings suggest a chloride binding site in an intramembrane pump sector. Chloride channels The underlying mechanisms for the differences in chloride requirements in different tissues have not been identified, and there is still some controversy as to the molecular identity of the associated Cl - -conducting proteins.

Some candidates have been identified, such as ClC family members and the cystic fibrosis transmembrane conductance regulator CFTR. Chloride channels are classified into the following categories: 1 the often voltage-gated ClC family, which includes the Gef1 protein of the yeast Saccharomyces cerevisiae Gef1p. The latter has been thought to provide the compensatory transport of Cl - anions to the lumen of the Golgi, thereby regulating the pH of this compartment 18 ; 2 CFTR; 3 ligand-gated GABA and glycine-activated Cl - channels; 4 calcium-activated chloride channels; 5 swelling-activated chloride channels, or volume-regulated anion channels 19, The ClC chloride channel family was initially identified by expression cloning of the voltage gated Cl - channel ClC-0 from the electrical organ of the Torpedo Since this initial cloning of the ClC family, nine mammalian ClCs have been cloned by using homology-based cloning methods The CFTR Cl - channel was identified as the protein encoded by the gene whose mutation results in cystic fibrosis, a lethal autosomal recessive disease common in populations of Caucasian or northern European descent A characteristic of the disease is the severely impaired Cl - transport across several epithelia.

In the airway of cystic fibrosis patients, fluid and electrolyte secretion is inhibited because of the defect in CFTR. This conclusion leads to a reinterpretation of the activation of Cl - currents by low pH in terms of proton transport rather than proton-dependent channel gating. At first sight, the advantage of a system of this kind is not apparent.

An exchanger will use more metabolic energy to produce a given pH gradient, but may establish a more constant internal Cl - concentration. The conclusion that the ClC family consists of channel and transporter subtypes, the former residing in plasma membranes and the latter in acidifying intracellular membranes, presented biophysicists with unusual behaviors. This suggests that membrane proteins with similar structures can support ion-transport mechanisms that are enormously different from a thermodynamic point of view Using a Cl - fluorescent indicator, Bae and Verkman 29 observed that in endocytic vesicles from rabbit proximal tubule the chloride conductance was activated by phosphorylation through a cyclic AMP cAMP -dependent protein kinase.

In isolated rabbit S3 proximal tubules, the apical insertion of V-ATPase-containing vesicles was shown to also be dependent on chloride, being delayed in the absence of the anion In proximal tubule cells, the co-localization of proton pumps with ClC-5 chloride channels in apical endosomes is related to an X-chromosome-linked disease characterized by low-molecular weight proteinuria, hypercalciuria and kidney stones, called Dent's disease 13, This syndrome is caused by mutations of the CLCN5 gene, predominantly expressed in kidney, which has been shown to decrease or abolish ClC-5 activity.

This channel conducts outwardly rectifying chloride currents that represent a counter-ion flux to the electrogenic influx of protons into the endosomes, suggesting that ClC-5 is essential for renal endocytosis These endosomes form part of the receptor-mediated endocytic pathway that transports proteins 13 , and therefore the lack of ClC-5 might impair endosomal acidification, compromising the reabsorption of filtered proteins and causing the proteinuria observed in Dent's disease The in vitro acidification of cortical renal endosomes prepared from ClC-5 KO mice was shown to be significantly reduced.

In addition, the loss of ClC-5 reduced apical fluid phase- and receptor-mediated endocytosis, as well as the endocytotic retrieval of plasma membrane proteins in a cell-autonomous manner These findings support the postulated importance of ClC-5 in endosomal acidification essential for protein reabsorption.

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The alterations observed in Dent's disease are not restricted to endosomal function. ClC-5 is involved in the plasma membrane insertion and recycling of these vesicles Thus, these data also suggest a role for ClC-5 in the proton secretion mechanism in these cells. ClC-5 lacks some features, for example activation by protein kinase A since chloride conductance in endosomes from proximal tubules is stimulated by this protein , suggesting that another conductance is involved 3. Recent studies have demonstrated that ClC-4 facilitates endosomal acidification and is important but not essential for the endocytosis process because ClC-4 KO mice do not display proteinuria The partial expression of ClC-4 and ClC-5 at the cell surface allowed the detection of strongly outwardly rectifying currents that depended on anions and pH.

Recently, Tararthuch et al. In contrast, no changes in the acidification rates of several intracellular organelles were demonstrable after activation of chloride currents stimulated by cAMP Liver By means of the measurement of the uptake of radioactive chloride into vesicles, Glickman et al. In rat liver multivesicular bodies an endosome intermediate between coated vesicles and lysosomes , chloride was found to increase the initial rate of vesicle acidification and to affect the relative chemical and electrical contributions of the steady-state pump proton-motive force Using highly enriched fractions of rat liver endosomes, Fuchs et al.

Although some investigators have demonstrated a role for chloride channels in the acidification of intracellular organelles in hepatocytes, the molecular identity of these channels remains poorly understood. Hara-Chikuma et al. These investigators found a functional ClC-3 Cl - conductance in endosomes of cell homogenates from wild-type versus ClCdeficient hepatocytes containing fluorescently labeled endosomes.

Central nervous system In rat brain synaptic vesicles, Glebov et al. In bovine brain clathrin-coated vesicles, acidification of the vesicle interior showed considerable anion selectivity Cl - greater than Br - much greater than NO 3 - much greater than gluconate, SO 2 - 4 , similar to HPO 2 - 4 and mannitol , but was relatively insensitive to cation replacement as long as Cl - was present Disruption of ClC-3 by generation of ClCdeficient mice present in endosomal compartments of synaptic vesicles has been shown to lead to a loss of hippocampus function characterized by postnatal growth retardation, blindness secondary to retinal degradation and behavioral abnormalities.

ClC-3 deficiency in mice led to elevated intraendosomal pH, which influenced the cellular protein degradation cascade, causing phenotypes similar to human neuronal ceroid lipofuscinosis a neurodegenerative disorder characterized by excessive accumulation of lipopigments Similarly to ClC-3, disruption of mouse ClC-6 and ClC-7 leads to neurodegeneration, with neurons displaying intracellular electron-dense deposits characteristic of lysosomal marker proteins Since ClC-6 and ClC-7 have a subcellular localization, it is possible that lysosomal storage observed in the respective KO mice is a consequence of defective late endosomal or lysosomal function.

The passive conductive Cl - transport was found to be due to an apparently unique Cl - channel, a mechanism participating in net vectorial HCl secretion by osteoclasts, for bone reabsorption Purification of this protein and reconstitution into phospholipid membranes retained the transport of Cl -. In , Schlesinger and colleagues 57 isolated a kDa Cl - channel from avian osteoclast ruffled border whose human homologue is the intracellular chloride channel 5 CLIC5 , one of a group of chloride channels expressed intracellularly and believed to act in acid secretion, but not correlated with human disease In planar bilayers, the ruffled border channel was found to be a stilbene sulfonate-inhibitable, outwardly rectifying chloride channel.

Regulation of Ca2+-ATPases,V-ATPases and F-ATPases | Sajal Chakraborti | Springer

Since outward rectification of a chloride channel means that the single channel conductance is greater for chloride entering than exiting the cell and the proposed function of this channel is to allow chloride to exit the cell in parallel with protons, outward rectification may seem contradictory. When the chloride conductance is limiting, proton pump activity hyperpolarizes the ruffled border membrane, increasing the internal negative potential in proportion to the pump activity.

If the ruffled border chloride channel were not rectifying, the proton pump-driven hyperpolarization would increase the chloride current and HCl transport. However, since the chloride channel is outwardly rectifying, changes in the membrane potential have a small effect on the chloride current and acid transport.

So, during bone reabsorption, when the electrogenic proton pump hyperpolarizes the ruffled border membrane, the number of active chloride channels in that membrane will directly determine and limit HCl transport While CLIC5 is not related to human disease, transgenic mice deficient in a chloride channel analogue, ClC-7, have osteopetrosis a rare inherited disorder whereby the bones harden, becoming denser ClC-7 is a mostly intracellular chloride channel from late endosomes and lysosomes. Since CLIC5 as well as ClC-7 have been immunolocalized to the ruffled border, and since both are members of families of known chloride channels and suppression of their expression leads to decreased bone resorption, it is possible that the regulation of acidification and bone resorption are complex processes with multiple sites where chloride transport can exert an influence.

CLIC5 and ClC-7 could be cooperating components of anion transport activity in the ruffled border membrane that supports bone resorption In addition, more recently, Okamoto et al. Colocalization of Cl - channels and this ATPase has been demonstrated in several tissues. This disease is related to a defect in the expression of ClC-5 channels or exchangers. Other diseases related to defects in Cl - channels have been described, including forms of neurodegeneration and osteopetrosis. Figure 1. The V-ATPase complex is composed of a peripheral domain V 1 , responsible for ATP hydrolysis, and an integral domain, responsible for proton translocation across the membrane.

The V 1 domain is a hexamer of A and B subunits.


The V 0 domain is composed of a ring of proteolipid subunits c, c' and c" , adjacent to subunits a and e. The V 1 and V 0 domains are connected by a central stalk, composed of subunits D and F of V 1 and subunit d of V 0 , and multiple peripheral stalks, composed of subunits C, E, G, H, and a. Modified from Ref. Annu Rev Physiol ; Malnic G. Physiol Rev ; Forgac M. Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology. Nat Rev Mol Cell Biol ; 8: Kane PM. Microbiol Mol Biol Rev ; The yeast lysosome-like vacuole: Endpoint and crossroads. Biochim Biophys Acta ; ahead of print; accessed February 16, J Biol Chem ; Mechanism of acidification along cortical distal tubule of the rat.

Am J Physiol ; FF Pflugers Arch ; Malnic G, Geibel JP. J Membr Biol ; Effect of bafilomycin on proximal bicarbonate absorption in the rat. Braz J Med Biol Res ; Identification and characterization of a proton pump on lysosomes by fluorescein-isothiocyanate-dextran fluorescence. ClC-5, the chloride channel mutated in Dent's disease, colocalizes with the proton pump in endocytotically active kidney cells.

J Cell Biol ; Mechanism of acidification of the trans-Golgi network TGN. Further, a 2V contributes in cisplatin mediated drug resistance in ovarian cancer and selective inhibition of a 2V could serve as an efficient strategy to treat chemo-resistant ovarian cancer [ 48 ]. Recently, Apicularen and archazolids have been reported to be potent and specific inhibitors of V-ATPase [ 49 ]. However, all available small molecule inhibitors have significant toxicity considering the involvement of V-ATPase in normal cell physiology [ 50 ].

Autophagy is the process of selective degradation or recycling of cargos delivered by autophagosomes to lysosomes [ 52 ]. Tumor cells show varied dependence on autophagy as they progress from primary tumor to the highly metastatic solid tumor [ 53 ]. Cellular cargo marked for degradation are delivered to the lysosomes by autophagic processes.

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The proton pumping activity of V-ATPase is responsible for activation of lysosomal acid hydrolases which degrade cargo uptake from autophagosomes [ 54 ]. Although studies point to the requirement of functional V-ATPase for autophagy [ 55 ] and V-ATPase inhibitor Bafilomycin is used as classic inhibitor of autophagy [ 56 ], the exact role of V-ATPase in membrane dynamics of autophagic flux is not understood.

The endolysosomal pathway is important for both positive and negative regulation of signaling pathways [ 8 , 58 ]. This can be attributed to the fact that Notch signaling depends on the endolysosomal pathway for its activation, maintenance and degradation of key pathway mediators [ 61 , 62 , 63 ]. V-ATPase maintains cellular pH balance and plays an important role in endocytosis, protease activation and protein degradation.

Following ligand binding, Notch receptor takes the endocytic route and is cleaved by proteases for activation. Later, the receptors are degraded in the lysosome [ 63 ]. In Drososphila, mutations in Vps25, a component of ESCRT machinery that regulates endosomal sorting of signaling receptors, causes accumulation of the Notch receptor in endosomes and enhances Notch signaling [ 64 ]. In a study analyzing drosophila mutations of Hrs, another component of ESCRT, Notch accumulates in endosomes but does not cause ectopic activation of Notch signaling [ 65 ].

The loss of autophagy leads to activation of the Notch signaling in the Drosophila ovarian follicle cells due to disruption of Notch degradation [ 66 ]. Contrary to these reports, an independent study found that mutations in Rabconnection-3 disrupt the proton-pumping activity of V-ATPase and accumulate Notch in late endosomes after S2 cleavage, thereby reducing Notch Signaling in Drosophila and mammalian cells [ 67 ]. These findings were followed by reports in Drosophila further indicating that through the acidification of endolysosomal pathway, V-ATPase is required for the activation of Notch in endosomes as well as for the degradation of Notch in lysosomes [ 68 ].

During mammalian development, expression of a dominant negative subunit of V-ATPase in neural precursors reduced Notch signaling and depleted neural stem cells leading to neuronal differentiation [ 69 ]. Recently, studies in astrocytes in the retina of Nuc1 mutated rats were shown to dysregulate Notch signaling. This is an interesting finding considering that the role of V-ATPase in vision in now emerging [ 26 ]. Together these findings indicate that the regulation of Notch signaling by V-ATPase can have both positive and negative outcomes depending on the cellular localization of V-ATPase activity affected endosomes vs lysosomes and the dependence of Notch receptor processing on the endosomal pathway [ 71 , 72 ].

Although the V-ATPase and Notch crosstalk has been investigated in the context of V-ATPase dependent endolysosomal acidification affecting Notch signaling, a recent report suggests that regulation could also be vice-versa. Our studies have identified that V-ATPase regulates Notch Signaling in breast cancer [ 74 ] and mammary gland development [ 75 ].

Loss of a 2V in mouse mammary gland leads to abnormal Notch activation and impairs ductal morphogenesis, causing lactation defects [ 75 ]. Further in preterm labor induced by inflammatory response to LPS injection, up-regulation of Notch-related inflammation and down-regulation of angiogenesis factors was observed [ 76 ]. This paves a way for important future direction especially since GSI is an efficient inhibitor of Notch Signaling and is currently in clinical trials for several cancers.

With this, the V-ATPase and Notch crosstalk emerges to be important during normal development and indiseases like Alzheimers and various cancers [ 78 ]. The Wnt signaling pathway plays a major role in cell and tissue maintenance, polarity and differentiation. In humans, dysregulation of Wnt signaling has been implicated in cancer [ 79 ].

A classic example of dysregulated Wnt signaling is colorectal cancer wherein the loss of Adenomatous Polyposis Coli APC , a negative regulator of Wnt signaling triggers tumorigenesis [ 80 ]. Mutations in the a2V gene cause Autosomal recessive Cutis Laxa ACL syndrome where patients present with decreased amount of extra cellular matrix proteins like Collagen resulting in wrinkly skin phenotype [ 86 ].

Supporting theses findings, a mechanistic investigation of the mutations responsible for cutis laxa in humans identified a2 PL mutation to be unstable and defective in golgi trafficking compared to wild type [ 87 ]. This suggests that the role of a 2V in modulating signaling mediators is not exclusive to Notch.

Further, these mice also displayed a reduction of total collagen due to impaired glycosylation [ 90 ]. Activated mTORC1 responds to growth factor signaling controls the regulatory switch from cell death to proliferation [ 94 ]. A recent report suggested the involvement of osteoclast proton pump regulator Atp6v1c1 in enhancing breast cancer growth by activating the mTORC1 pathway and bone metastasis by increasing V-ATPase activity [ 95 ]. However, there are other steps of the signaling pathways known to be pH dependent, which warrant future investigation.

We and others have shown that surface expression of V-ATPase modulates MMPs thereby leading the proliferation ofcancer cells [ 43 , 48 ]. Similarly, the involvement of V-ATPase in activation of acid proteases during lysosomal degradation to regulate signal turnover cannot be ignored [ 96 ] See summary Fig. V-ATPase could have profound effects on cell fate by influencing signaling molecules that depend on pH. The research on V-ATPase regulation of signaling pathways is a field waiting to be explored that will have a tremendous impact in physiology and pathology.

The mechanistic basis of V-ATPase dependent signaling. In Notch Signaling, the Notch receptor dark pink is cleaved in Golgi and translocated to the plasma membrane where further cleavage of the receptor occurs in response to Notch ligand light pink binding. Cleaved Notch intracellular domain is translocated to nucleus activating Notch target genes. Forgac M. Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology.

Nat Rev Mol Cell Biol. Recent insights into the structure, regulation, and function of the V-ATPases. Trends Biochem Sci. Eukaryotic V-ATPase: novel structural findings and functional insights. Biochim Biophys Acta.

Regulation of Ca2+-ATPases,V-ATPases and F-ATPases

The function of V-ATPases in cancer. Physiol Rev. Nishi T, Forgac M. A structural model of the vacuolar ATPase from transmission electron microscopy. Shao E, Forgac M. Involvement of the nonhomologous region of subunit a of the yeast V-ATPase in coupling and in vivo dissociation. J Biol Chem. Marshansky V, Futai M. Curr Opin Cell Biol. Holliday LS. New Journal of Science. Scott CC, Gruenberg J. Ion flux and the function of endosomes and lysosomes: pH is just the start: the flux of ions across endosomal membranes influences endosome function not only through regulation of the luminal pH.

Endocytic recycling. Saftig P, Klumperman J. Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function.


J Cell Biol. Nat Genet. Commun Integr Biol. EMBO J. Breton S, Brown D. New insights into the regulation of V-ATPase-dependent proton secretion. Am J Physiol Renal Physiol. Regulation of the V-ATPase in kidney epithelial cells: dual role in acid-base homeostasis and vesicle trafficking. J Exp Biol. Karet FE. Physiological and metabolic implications of V-ATPase isoforms in the kidney.

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Physiology Bethesda. Male fertility and apoptosis in normal spermatogenesis are regulated by vacuolar-ATPase isoform a2. J Reprod Immunol. V-ATPases in osteoclasts: structure, function and potential inhibitors of bone resorption. Int J Biochem Cell Biol. V-ATPase expression in the mouse olfactory epithelium. Am J Physiol Cell Physiol. Atp6v0a4 knockout mouse is a model of distal renal tubular acidosis with hearing loss, with additional extrarenal phenotype.

Vacuolar ATPases and their role in vision. Adv Exp Med Biol. Regulation of luminal acidification by the V-ATPase. Kartner N, Manolson MF. Expert Opin Drug Discov. Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump kD subunit, cause recessive distal renal tubular acidosis with preserved hearing. V-ATPase upregulation during early pregnancy: a possible link to establishment of an inflammatory response during preimplantation period of pregnancy.

Tumor-associated a2 vacuolar ATPase acts as a key mediator of cancer-related inflammation by inducing pro-tumorigenic properties in monocytes. J Immunol. Inhibition of vacuolar ATPase subunit in tumor cells delays tumor growth by decreasing the essential macrophage population in the tumor microenvironment. Expression and role of a2 vacuolar-ATPase a2V in trafficking of human neutrophil granules and exocytosis.

J Leukoc Biol. Sci Rep. The Warburg effect: how does it benefit cancer cells? Anti-Cancer Drugs. Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question. Causes and consequences of increased glucose metabolism of cancers.

J Nucl Med. V-ATPase inhibition by archazolid leads to lysosomal dysfunction resulting in impaired cathepsin B activation in vivo. Int J Cancer. Kubota S, Seyama Y. Biochem Biophys Res Commun. J Cell Biochem. Presenilin-1, nicastrin, amyloid precursor protein, and gamma-secretase activity are co-localized in the lysosomal membrane. Drug resistance and cellular adaptation to tumor acidic pH microenvironment. Mol Pharm. Elevated expression of vacuolar proton pump genes and cellular PH in cisplatin resistance.

The expression of V-ATPase is associated with drug resistance and pathology of non-small-cell lung cancer. Diagn Pathol.


Cancer Res. Huss M, Wieczorek H. Inhibitors of V-ATPases: old and new players. Defective acidification in human breast tumor cells and implications for chemotherapy. J Exp Med. Autophagy--a key player in cellular and body metabolism. Nat Rev Endocrinol. Gewirtz DA. The four faces of autophagy: implications for cancer therapy. Vacuolar ATPase in phagosome-lysosome fusion. V-ATPase engagement in autophagic processes. Bafilomycins produced in culture by Streptomyces spp.

J Nat Prod. Autophagosome-lysosome fusion is independent of V-ATPase-mediated acidification. Nat Commun.