Selective Inhibition of Osteoclast Vacuolar H+-ATPase

Farina, Carlo; Gagliardi, Stefania

doi:10.2174/1381612023393369

Cited by 91 publications

(48 citation statements)

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“…First, for determining the appropriate concentration of bafilomycin for the inhibition of V-ATPase, the response of cells to bafilomycin at concentrations ranging from 10 Ϫ1 to 10 Ϫ8 M was examined for inhibitory effect on V-ATPase. Consistent with previous reports (32,33), the 50% inhibitory concentration (IC 50 ) of bafilomycin for V-ATPase was ϳ10 -100 nM (supplemental Fig. 4).…”

Section: V-atpase Inhibitor Reverses the Effects Of Bi-1 Which Are Rsupporting

confidence: 92%

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Enhanced Lysosomal Activity Is Involved in Bax Inhibitor-1-induced Regulation of the Endoplasmic Reticulum (ER) Stress Response and Cell Death against ER Stress

Lee

Kim

et al. 2011

Journal of Biological Chemistry

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Bax inhibitor-1 (BI-1) is an evolutionarily conserved protein that protects cells against endoplasmic reticulum (ER) stress while also affecting the ER stress response. In this study, we examined BI-1-induced regulation of the ER stress response as well as the control of the protein over cell death under ER stress. In BI-1-overexpressing cells (BI-1 cells), proteasome activity was similar to that of control cells; however, the lysosomal fraction of BI-1 cells showed sensitivity to degradation of BSA. In addition, areas and polygonal lengths of lysosomes were greater in BI-1 cells than in control cells, as assessed by fluorescence and electron microscopy. In BI-1 cells, lysosomal pH was lower than in control cells and lysosomal vacuolar H ؉ -ATPase(V-ATPase), a proton pump, was activated, suggesting high H ؉ uptake into lysosomes. Even when exposed to ER stress, BI-1 cells maintained high levels of lysosomal activities, including V-ATPase activity. Bafilomycin, a V-ATPase inhibitor, leads to the reversal of BI-1-induced regulation of ER stress response and cell death due to ER stress. In BI-1 knock-out mouse embryo fibroblasts, lysosomal activity and number per cell were relatively lower than in BI-1 wild-type cells. This study suggests that highly maintained lysosomal activity may be one of the mechanisms by which BI-1 exerts its regulatory effects on the ER stress response and cell death.Eukaryotic cells respond to the threat of protein misfolding in the endoplasmic reticulum (ER) 3 by activating either the ER stress response or the unfolded protein response (UPR) (1, 2). The ER stress response consists of pathways that inhibit protein synthesis, up-regulate chaperone proteins, and increase protein degradation activity. Initiation of the ER stress response occurs when the quantity of unfolded proteins exceeds the capacity of chaperone proteins. GRP78 normally binds to the N-terminal ends of the following three transmembrane proteins: RNAdependent protein kinase-like ER kinase, inositol-requiring enzyme 1␣ (IRE1␣), and activating transcription factor 6 (ATF6) (3, 4). Protein kinase-like ER kinase phosphorylates eukaryotic initiation factor 2␣ (eIF2␣) in the regulation of protein translation (5). IRE1 is related to genes involved in the transport of unfolded proteins out of the ER and in their degradation by ER-associated degradation (ERAD) (6). ATF6␣ can also induce chaperone proteins and precedes IRE1␣-mediated production of the ERAD pathway (6). Lysosomal activity is an ERAD II pathway, whereas ERAD I is a proteasome/ubiquitination pathway (7). The ERAD mechanism increases the protein folding capacity by reducing protein folding loads (7, 8), implying that ERAD is a physiological pathway that can regulate ER stress responses (8, 9).Bax inhibitor-1 (BI-1, also known as a "testis-enhanced gene transcript") is an anti-apoptotic protein that inhibits the activation of Bax and its translocation to the mitochondria (10). Functionally, BI-1 affects Ca 2ϩ leakage from the ER, as measured by Ca 2ϩ -sensitive ER-targete...

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Section: V-atpase Inhibitor Reverses the Effects Of Bi-1 Which Are Rsupporting

confidence: 92%

“…4D). The inhibition of the lysosomal activity was clearly shown in the presence of bafilomycin, a potent and specific V-ATPase inhibitor (32,33).…”

Section: Resultsmentioning

confidence: 99%

Enhanced Lysosomal Activity Is Involved in Bax Inhibitor-1-induced Regulation of the Endoplasmic Reticulum (ER) Stress Response and Cell Death against ER Stress

Lee

Kim

et al. 2011

Journal of Biological Chemistry

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“…A high rate of proton transport by the V-ATPase appears to be a key element in the development of diseases such as osteoporosis and in the growth of certain types of tumors. These findings have led to an investigation of the use of V-ATPase inhibitors as therapeutic drugs (8,9).…”

mentioning

confidence: 99%

A Model for the Proteolipid Ring and Bafilomycin/Concanamycin-binding Site in the Vacuolar ATPase ofNeurospora crassa

Bowman¹,

McCall²,

Baertsch³

et al. 2006

J. Biol. Chem.

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The vacuolar ATPase has been implicated in a variety of physiological processes in eukaryotic cells. Bafilomycin and concanamycin, highly potent and specific inhibitors of the vacuolar ATPase, have been widely used to investigate the enzyme. Derivatives have been developed as possible therapeutic drugs. We have used random mutagenesis and site-directed mutagenesis to identify 23 residues in the c subunit involved in binding these drugs. We generated a model for the structure of the ring of c subunits in Neurospora crassa by using data from the crystal structure of the homologous subunits of the bacterium Enterococcus hirae (Murata, T., Yamato, I., Kakinuma, Y., Leslie, A. G., and Walker, J. E. (2005) Science 308, 654 -659). In the model 10 of the 11 mutation sites that confer the highest degree of resistance are closely clustered. They form a putative drug-binding pocket at the interface between helices 1 and 2 on one c subunit and helix 4 of the adjacent c subunit. The excellent fit of the N. crassa sequence to the E. hirae structure and the degree to which the structural model predicts the clustering of these residues suggest that the folding of the bacterial and eukaryotic polypeptides is very similar. The vacuolar ATPase (V-ATPase)2 is a component of almost all the eukaryotic cell membranes derived from the endoplasmic reticulum, e.g. Golgi, vacuoles, and coated vesicles (1-4). It generates an electrochemical gradient for protons, providing a driving force for metabolite transport. It also plays a major role in adjusting the pH within organelles.In animals many diverse physiological processes depend on the function of the V-ATPase. For example, a single mutation of the enzyme in humans was shown to cause both loss of kidney function and deafness (5). The V-ATPase is critical for the growth of bone (6), and overexpression of the enzyme has been correlated with the metastasis of breast cancer cells (7). The common thread linking these physiological events is secretion of protons by specialized cells that have high amounts of V-ATPase in the plasma membrane. A high rate of proton transport by the V-ATPase appears to be a key element in the development of diseases such as osteoporosis and in the growth of certain types of tumors. These findings have led to an investigation of the use of V-ATPase inhibitors as therapeutic drugs (8, 9).Several different classes of natural products, such as the benzolactone enamides and the chondropsins, have been shown to be potent and specific inhibitors of V-ATPases (10 -12). The most widely used inhibitors are two similar macrolide antibiotics, bafilomycin and concanamycin. These molecules inhibit the V-ATPase from all eukaryotic cells that have been tested, typically with half-maximal inhibition at 0.1-5 nM when assayed in vitro (13-15). At higher concentrations these antibiotics also inhibit in vivo, and derivatives of bafilomycin were effective in treating osteoporosis in a rat model system (16).We have been trying to identify the site on the V-ATPase at which bafilomycin an...

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“…Pourtant, une étude réalisée chez des volontaires sains et utilisant une mesure directe de l'absorption intestinale du calcium a montré que l'oméprazole ne modifiait pas cette absorption [10]. À l'inverse, d'autres auteurs ont mis en évidence un effet positif des IPP sur la résorption osseuse via une inhibition d'une pompe à proton au niveau des ostéoclastes [11]. Ces données semblent concorder avec les résultats de Gray et al qui n'ont pas observé de variation significative de la densité minérale osseuse dans leur étude et font l'hypothèse que l'effet direct des IPP sur la résorption osseuse pourrait compenser leur impact négatif sur l'absorption intestinale du calcium [6].…”

Section: Risque Fracturaireunclassified

Effets indésirables des inhibiteurs de la pompe à proton : faut-il craindre de les prescrire au long cours ?

Roulet

Vernaz

Giostra

et al. 2012

La Revue de Médecine Interne

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Mots clés :Inhibiteurs de la pompe à proton Fractures ostéoporotiques Infections Cancer gastrique Pharmacodépendance r é s u m é La prévalence des traitements de longue durée par inhibiteurs de la pompe à proton (IPP) est en augmentation. Si leur tolérance à court terme est bonne, des réserves ont vu le jour sur d'éventuels effets indésirables graves associés à une exposition prolongée. Ainsi, l'association avec le risque fracturaire semble être confirmée, notamment au niveau vertébral, ainsi que le risque d'effet rebond sur la sécrétion acide à l'arrêt du traitement. Le risque de pneumopathie communautaire n'est pas établi dans la population générale et semble limité aux patients les plus fragiles. L'association avec le risque d'infection digestive à Clostridium difficile est probable. Les cas de néphrite tubulo-intestitielle sont rares mais peuvent conduire à une insuffisance rénale chronique. Les données disponibles sont encore insuffisantes pour évaluer le risque de carence en vitamine B12, en fer ou en magnésium et le risque de cancer digestif, même si des bases physiopathologiques existent dans le cas du cancer gastrique. Il existe des interactions avec de nombreux autres médicaments, notamment ceux qui sont métabolisés par certaines isoenzymes du cytochrome P450. Enfin, la balance bénéfice-risque de l'utilisation des IPP au long cours chez l'enfant semble défavorable dans la plupart des cas.© 2012 Société nationale française de médecine interne (SNFMI). Publié par Elsevier Masson SAS. Tous droits réservés. Keywords: Proton pump inhibitors Osteoporotic fractures Infection Stomach neoplasms Substance withdrawal syndrome a b s t r a c tLong-term treatment with proton pump inhibitors (PPI) is becoming more prevalent. Although they are well tolerated in the short term, serious concerns about long-term use have arisen. Recent data suggest that the latter is associated with an increased risk for osteoporotic fracture (especially vertebral), Clostridium difficile infection and rebound acid hypersecretion after treatment discontinuation. Acute interstitial nephritis is rare but may progress to chronic renal failure. An increased risk of communityacquired pneumonia has not been established in the general population and seems limited to the most vulnerable patients. Consistent data are still missing to correctly assess the risk of iron deficiency, vitamin B12 deficiency or hypomagnesaemia and the risk of digestive malignant diseases, despite the pathophysiological basis that exists concerning gastric malignancy. Many drug interactions can occur on long-term treatment, including some that imply the cytochrome P450 enzymes. Finally, the risk-benefit balance for a chronic PPI use in children seems unfavorable in most cases.

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Selective Inhibition of Osteoclast Vacuolar H+-ATPase

Cited by 91 publications

References 0 publications

Enhanced Lysosomal Activity Is Involved in Bax Inhibitor-1-induced Regulation of the Endoplasmic Reticulum (ER) Stress Response and Cell Death against ER Stress

Enhanced Lysosomal Activity Is Involved in Bax Inhibitor-1-induced Regulation of the Endoplasmic Reticulum (ER) Stress Response and Cell Death against ER Stress

A Model for the Proteolipid Ring and Bafilomycin/Concanamycin-binding Site in the Vacuolar ATPase ofNeurospora crassa

Effets indésirables des inhibiteurs de la pompe à proton : faut-il craindre de les prescrire au long cours ?

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