Concanamycin B, a Vacuolar H+-ATPase Specific Inhibitor Suppresses Bone Resorption in Vitro.

Woo, Je‐Tae; Ohba, Yasuo; Tagami, Kahori; Sumitani, Koji; Yamaguchi, Kohji; Tsuji, Tomoko

doi:10.1248/bpb.19.297

Cited by 14 publications

(13 citation statements)

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“…Inhibition of H + -V-ATPase by concanamycin (Woo et al, 1996) or DCCD (Finbow et al, 1993) specifically randomized the localization of Shh and Nodal (Fig. 6A-D) Concanamycin induced aberrant sidedness of Shh expression in 67%, and Nodal in 24%, of embryos (Table 4).…”

Section: Developmentmentioning

confidence: 90%

Early, H+-V-ATPase-dependent proton flux is necessary for consistent left-right patterning of non-mammalian vertebrates

Adams

Robinson

Fukumoto³

et al. 2006

Development

251

306

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Biased left-right asymmetry is a fascinating and medically important phenomenon. We provide molecular genetic and physiological characterization of a novel, conserved, early, biophysical event that is crucial for correct asymmetry: H + flux. A pharmacological screen implicated the H + -pump H + -V-ATPase in Xenopus asymmetry, where it acts upstream of early asymmetric markers. Immunohistochemistry revealed an actin-dependent asymmetry of H + -V-ATPase subunits during the first three cleavages. H + -flux across plasma membranes is also asymmetric at the four-and eight-cell stages, and this asymmetry requires H + -V-ATPase activity. Abolishing the asymmetry in H + flux, using a dominant-negative subunit of the H + -V-ATPase or an ectopic H + pump, randomized embryonic situs without causing any other defects. To understand the mechanism of action of H + -V-ATPase, we isolated its two physiological functions, cytoplasmic pH and membrane voltage (V mem ) regulation. Varying either pH or V mem , independently of direct manipulation of H + -V-ATPase, caused disruptions of normal asymmetry, suggesting roles for both functions. V-ATPase inhibition also abolished the normal early localization of serotonin, functionally linking these two early asymmetry pathways. The involvement of H + -V-ATPase in asymmetry is conserved to chick and zebrafish. Inhibition of the H + -V-ATPase induces heterotaxia in both species; in chick, H + -V-ATPase activity is upstream of Shh; in fish, it is upstream of Kupffer's vesicle and Spaw expression. Our data implicate H + -V-ATPase activity in patterning the LR axis of vertebrates and reveal mechanisms upstream and downstream of its activity. We propose a pH-and V mem -dependent model of the early physiology of LR patterning. Development 133, 1657Development 133, -1671Development 133, (2006 DEVELOPMENT 1658 necessary to characterize the endogenous behavior of the relevant pumps in embryos and to place their function in the context of known LR patterning mechanisms. Here, we explore the properties of H + -V-ATPase function in several vertebrate embryos. Through endogenous localization of the H + -V-ATPase and gain-and loss-offunction experiments in chick, frog and zebrafish, we identify the H + -V-ATPase as a novel, conserved, obligate component of LR patterning upstream of asymmetric gene expression. KEY WORDS: Left-right asymmetry, H + -V-ATPase, V-ATPase, Xenopus, Chick, Zebrafish, Axial patterning, Cytoplasmic pH, Membrane voltage MATERIALS AND METHODS Animal husbandryXenopus embryos were collected according to standard protocols (Sive et al., 2000) in 0.1ϫ Modified Marc's Ringers (MMR) pH 7.8 + 0.1% Gentamicin. Xenopus embryos were staged according to Nieuwkoop and Faber (Nieuwkoop and Faber, 1967). Chick embryos from Charles River Laboratories, maintained at 38°C, were staged according to Hamburger and Hamilton (Hamburger and Hamilton, 1992). Zebrafish embryos (Westerfield, 1995) were maintained at 28.5°C in water containing 1 drop per gallon Methyl Blue. Assaying organ situsXenopus e...

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Section: Developmentmentioning

confidence: 90%

Early, H+-V-ATPase-dependent proton flux is necessary for consistent left-right patterning of non-mammalian vertebrates

Adams

Robinson

Fukumoto³

et al. 2006

Development

251

306

View full text Add to dashboard Cite

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“…; Woo et al . ; Gagliardi et al ). The novel and specific inhibitor of osteoclastic vATPase SB‐242784 ((2Z,4E)‐5‐(5,6‐dichloro‐2‐indolyl)‐2‐methoxy‐N‐(1,2,2,6,6‐pentamethylpiperidin‐4‐yl)‐2,4‐penta‐dienamide) (NiKem Res.…”

Section: Methodsmentioning

confidence: 98%

Vacuole dynamics in the salivary glands ofDrosophila melanogasterduring prepupal development

Farkas

Beňová-Liszeková

Mentelová

et al. 2015

Develop. Growth Differ.

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A central function of the Drosophila salivary glands (SGs), historically known for their polytene chromosomes, is to produce and then release during pupariation the secretory glue used to affix a newly formed puparium to a substrate. This essential event in the life history of Drosophila is regulated by the steroid hormone ecdysone in the late-larval period. Ecdysone triggers a cascade of sequential gene activation that leads to glue secretion and initiates the developmentally-regulated programmed cell death (PCD) of the larval salivary glands, which culminates 16 h after puparium formation (APF). We demonstrate here that, even after the larval salivary glands have completed what is perceived to be one of their major biological functions -glue secretion during pupariation -they remain dynamic and physiologically active up until the execution phase of PCD. We have used specific metabolic inhibitors and genetic tools, including mutations or transgenes for shi, Rab5, Rab11, vha55, vha68-2, vha36-1, syx1A, syx4, and Vps35 to characterize the dramatic series of cellular changes occurring in the SG cells between pupariation and 7-8 h APF. Early in the prepupal period, they are remarkably active in endocytosis, forming acidic vacuoles. Midway through the prepupal period, there is abundant late endosomal trafficking and vacuole growth, which is followed later by vacuole neutralization and disappearance via membrane consolidation. This work provides new insights into the function of Drosophila SGs during the early-to mid-prepupal period.

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“…We previously reported that prodigiosin 25-C uncouples vacuolar type H(+)-ATPase, inhibits vacuolar acidification, and affects glycoprotein processing and that concanamycin B inhibits the acidification of endosomes and lysosomes induced by V-ATPase in macrophage J774 (30,31). We further found that prodigiosin 25-C and concanamycin B inhibit osteoclastic bone resorption on bone slices (32,33). Prodigiosin 25-C and concanamycin B are an uncoupler and a specific inhibitor, respectively, of vacuolar H + -ATPase.…”

Section: Effects Of Fk506 and Cyclosporin A On Osteoclast Differentiamentioning

confidence: 62%

Pharmacological Topics of Bone Metabolism: Antiresorptive Microbial Compounds That Inhibit Osteoclast Differentiation, Function, and Survival

et al. 2008

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Abstract. The mass and function of bones depends on the maintenance of a complicated balance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Osteoporosis typically reflects an imbalance in skeletal turnover, such that bone resorption exceeds bone formation. Osteoclasts are target cells for anti-osteoporosis therapies. To discover new types of antiresorptive agents, we screened for natural compounds that regulate osteoclast differentiation, function, and survival. As a result, we identified reveromycin A, destruxins, mevastatin, FK506, cyclosporin A, prodigiosins, concanamycins, and symbioimine among microbial natural compounds. In this review, we discuss the mechanisms of action of these compounds on osteoclasts.

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Concanamycin B, a Vacuolar H+-ATPase Specific Inhibitor Suppresses Bone Resorption in Vitro.

Cited by 14 publications

References 0 publications

Early, H+-V-ATPase-dependent proton flux is necessary for consistent left-right patterning of non-mammalian vertebrates

Early, H+-V-ATPase-dependent proton flux is necessary for consistent left-right patterning of non-mammalian vertebrates

Vacuole dynamics in the salivary glands ofDrosophila melanogasterduring prepupal development

Pharmacological Topics of Bone Metabolism: Antiresorptive Microbial Compounds That Inhibit Osteoclast Differentiation, Function, and Survival

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