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Ciliobrevin D Sale

目录号 : GC39359

Ciliobrevin D (compound 5) is a cell-permeable, reversible and specific antagonist of AAA+ (ATPases associated with diverse cellular activities) ATPase motor cytoplasmic dynein. Ciliobrevin D perturbs primary cilia formation and blocks Hedgehog (Hh) signaling.

Ciliobrevin D Chemical Structure

Cas No.:1370554-01-0

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10mM (in 1mL DMSO)
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产品描述

Ciliobrevin D (compound 5) is a cell-permeable, reversible and specific antagonist of AAA+ (ATPases associated with diverse cellular activities) ATPase motor cytoplasmic dynein. Ciliobrevin D perturbs primary cilia formation and blocks Hedgehog (Hh) signaling.

Ciliobrevin D inactivate dynein in Sertoli cells. The inactivation of dynein by ciliobrevin D also perturbs gross disruption of F-actin across the Sertoli cells in vitro.[2] Ciliobrevin D perturbs protein trafficking within the primary cilium, leading to their malformation and Hedgehog signaling blockade. Ciliobrevin D also prevents spindle pole focusing, kinetochore-microtubule attachment, melanosome aggregation, and peroxisome motility in cultured cells.[1]

Ciliobrevin D inactivate dynein in the testis. The inactivation of dynein by ciliobrevin D also perturbs gross disruption of F-actin across the seminiferous epithelium in vivo, illustrating there are cross talks between the two cytoskeletons in the testis.[2]

[1] Ari J Firestone, et al. Nature. 2012 Mar 18;484(7392):125-9. [2] Qing Wen, et al. Am J Physiol Endocrinol Metab. 2018 Nov 1;315(5):E924-E948.

Chemical Properties

Cas No. 1370554-01-0 SDF
Canonical SMILES O=C(C1=C(C=C(Cl)C=C1)Cl)/C(C#N)=C(N2)/NC3=CC(Cl)=CC=C3C2=O
分子式 C17H8Cl3N3O2 分子量 392.62
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1 mM 2.547 mL 12.735 mL 25.4699 mL
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10 mM 0.2547 mL 1.2735 mL 2.547 mL
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Research Update

The dynein inhibitor Ciliobrevin D inhibits the bidirectional transport of organelles along sensory axons and impairs NGF-mediated regulation of growth cones and axon branches

Dev Neurobiol 2015 Jul;75(7):757-77.PMID:25404503DOI:10.1002/dneu.22246.

The axonal transport of organelles is critical for the development, maintenance, and survival of neurons, and its dysfunction has been implicated in several neurodegenerative diseases. Retrograde axon transport is mediated by the motor protein dynein. In this study, using embryonic chicken dorsal root ganglion neurons, we investigate the effects of Ciliobrevin D, a pharmacological dynein inhibitor, on the transport of axonal organelles, axon extension, nerve growth factor (NGF)-induced branching and growth cone expansion, and axon thinning in response to actin filament depolymerization. Live imaging of mitochondria, lysosomes, and Golgi-derived vesicles in axons revealed that both the retrograde and anterograde transport of these organelles was inhibited by treatment with Ciliobrevin D. Treatment with Ciliobrevin D reversibly inhibits axon extension and transport, with effects detectable within the first 20 min of treatment. NGF induces growth cone expansion, axonal filopodia formation and branching. Ciliobrevin D prevented NGF-induced formation of axonal filopodia and branching but not growth cone expansion. Finally, we report that the retrograde reorganization of the axonal cytoplasm which occurs on actin filament depolymerization is inhibited by treatment with Ciliobrevin D, indicating a role for microtubule based transport in this process, as well as Ciliobrevin D accelerating Wallerian degeneration. This study identifies Ciliobrevin D as an inhibitor of the bidirectional transport of multiple axonal organelles, indicating this drug may be a valuable tool for both the study of dynein function and a first pass analysis of the role of axonal transport.

Dynein Coordinates β2-Adrenoceptor-Mediated Relaxation in Normotensive and Hypertensive Rat Mesenteric Arteries

Hypertension 2022 Oct;79(10):2214-2227.PMID:35929419DOI:10.1161/HYPERTENSIONAHA.122.19351.

Background: The voltage-gated potassium channel (Kv)7.4 and Kv7.5 channels contribute to the β-adrenoceptor-mediated vasodilatation. In arteries from hypertensive rodents, the Kv7.4 channel is downregulated and function attenuated, which contributes to the reduced β-adrenoceptor-mediated vasodilatation observed in these arteries. Recently, we showed that disruption of the microtubule network, with colchicine, or inhibition of the microtubule motor protein, dynein, with Ciliobrevin D, enhanced the membrane abundance and function of Kv7.4 channels in rat mesenteric arteries. This study aimed to determine whether these pharmacological compounds can improve Kv7.4 function in third-order mesenteric arteries from the spontaneously hypertensive rat, thereby restoring the β-adrenoceptor-mediated vasodilatation. Methods: Wire and intravital myography was performed on normotensive and hypertensive male rat mesenteric arteries and immunostaining was performed on isolated smooth muscle cells from the same arteries. Results: Using wire and intravital microscopy, we show that Ciliobrevin D enhanced the β-adrenoceptor-mediated vasodilatation by isoprenaline. This effect was inhibited partially by the Kv7 channel blocker linopirdine and was dependent on an increased functional contribution of the β2-adrenoceptor to the isoprenaline-mediated relaxation. In mesenteric arteries from the spontaneously hypertensive rat, Ciliobrevin D and colchicine both improved the isoprenaline-mediated vasorelaxation and relaxation to the Kv7.2 -7.5 activator, ML213. Immunostaining confirmed Ciliobrevin D enhanced the membrane abundance of Kv7.4. As well as an increase in the function of Kv7.4, the functional changes were associated with an increase in the contribution of β2-adrenoceptor following isoprenaline treatment. Immunostaining experiments showed Ciliobrevin D prevented isoprenaline-mediated internalizationof the β2-adrenoceptor. Conclusions: Overall, these data show that colchicine and Ciliobrevin D can induce a β2-adrenoceptor-mediated vasodilatation in arteries from the spontaneously hypertensive rat as well as reinstating Kv7.4 channel function.

Dynein regulates Kv7.4 channel trafficking from the cell membrane

J Gen Physiol 2021 Mar 1;153(3):e202012760.PMID:33533890DOI:10.1085/jgp.202012760.

The dynein motor protein transports proteins away from the cell membrane along the microtubule network. Recently, we found the microtubule network was important for regulating the membrane abundance of voltage-gated Kv7.4 potassium channels in vascular smooth muscle. Here, we aimed to investigate the influence of dynein on the microtubule-dependent internalization of the Kv7.4 channel. Patch-clamp recordings from HEK293B cells showed Kv7.4 currents were increased after inhibiting dynein function with Ciliobrevin D or by coexpressing p50/dynamitin, which specifically interferes with dynein motor function. Mutation of a dynein-binding site in the Kv7.4 C terminus increased the Kv7.4 current and prevented p50 interference. Structured illumination microscopy, proximity ligation assays, and coimmunoprecipitation showed colocalization of Kv7.4 and dynein in mesenteric artery myocytes. Ciliobrevin D enhanced mesenteric artery relaxation to activators of Kv7.2-Kv7.5 channels and increased membrane abundance of Kv7.4 protein in isolated smooth muscle cells and HEK293B cells. Ciliobrevin D failed to enhance the negligible S-1-mediated relaxations after morpholino-mediated knockdown of Kv7.4. Mass spectrometry revealed an interaction of dynein with caveolin-1, confirmed using proximity ligation and coimmunoprecipitation assays, which also provided evidence for interaction of caveolin-1 with Kv7.4, confirming that Kv7.4 channels are localized to caveolae in mesenteric artery myocytes. Lastly, cholesterol depletion reduced the interaction of Kv7.4 with caveolin-1 and dynein while increasing the overall membrane expression of Kv7.4, although it attenuated the Kv7.4 current in oocytes and interfered with the action of Ciliobrevin D and channel activators in arterial segments. Overall, this study shows that dynein can traffic Kv7.4 channels in vascular smooth muscle in a mechanism dependent on cholesterol-rich caveolae.

Primary cilia on porcine testicular somatic cells and their role in hedgehog signaling and tubular morphogenesis in vitro

Cell Tissue Res 2017 Apr;368(1):215-223.PMID:27841005DOI:10.1007/s00441-016-2523-6.

The primary cilium is a microtubule-based sensory organelle found on nearly all eukaryotic cells but little is understood about its function in the testis. We investigate the role of primary cilia on testis cells in vitro by inhibiting formation of the primary cilium with Ciliobrevin D, a cell-permeable, reversible chemical inhibitor of ATPase motor cytoplasmic dynein. We analyzed cultured cells for the presence of primary cilia and their involvement in hedgehog signaling. Primary cilia were present on 89.3 ± 2.3 % of untreated testicular somatic cells compared to 3.1 ± 2.5 % cells with primary cilia for Ciliobrevin D-treated cells. Protein levels of Gli-2 and Smoothened were lower on Western blots after suppression of cilia with Ciliobrevin D. The inhibitor did not affect centrosome localization or cell proliferation, indicating that changes were due to ablation of the primary cilium. Testicular somatic cells have the ability to form three-dimensional tubules in vitro. In vitro-formed tubules were significantly longer and wider in the control group than in the Ciliobrevin D-treated group (9.91 ± 0.35 vs. 5.540 ± 1.08 mm and 339.8 ± 55.78 vs. 127.2 ± 11.9 μm, respectively) indicating that primary cilia play a role in tubule formation. Our results establish that the inhibition of ATPase motor cytoplasmic dynein perturbs formation of primary cilia in testicular somatic cells, affects the hedgehog signaling pathway and impairs tubule formation in vitro. These findings provide evidence for a role of cilia in the testis in cell signaling and tubular morphogenesis in vitro.

Vesicle traffic in the outer hair cell

Eur J Neurosci 2021 Aug;54(3):4755-4767.PMID:34043848DOI:10.1111/ejn.15331.

The plasma-membrane marker FM1-43 was employed to reveal the relative significance of different types of endocytic and transcytic mechanisms in outer hair cells (OHCs) of the guinea-pig cochlea. A double-barrel local perfusion system was used to label independently the apical or synaptic pole of the isolated OHC to study mechanisms of vesicle uptake at the poles and of vesicle trafficking along and across the cell. Treatment with an inhibitor of macropino- and phagocytosis, phenylarsine oxide, or of clathrin-mediated endocytic activity, concanavalin A, significantly reduced the dye uptake at both the apical and the synaptic poles, indicating the presence of both clathrin-independent and clathrin-mediated processes at both poles. However, measurement of uptake speed in the presence of the inhibitors suggested that clathrin-independent processes contribute more extensively to endocytosis at the basal pole than the apical pole. Treatment with an inhibitor of myosin VI, 2,4,6-triiodophenol, significantly delayed both the apicobasal and the basoapical fluorescence signals. However, treatment with an inhibitor of kinesin, monastrol, or of dynein, Ciliobrevin D, significantly delayed the signals only in the basoapical direction. The myosinVI inhibitor, but neither the kinesin nor dynein inhibitors, significantly delayed the signals to the subsurface cisternae. That is, myosin VI carries vesicles in both longitudinal directions as well as radially to the subsurface cisternae, whereas kinesin and dynein participate primarily in basoapical trafficking. This fundamental information is essential for elucidating recycling mechanisms of specific proteins involved in establishing, controlling and maintaining the electromechanical action of OHCs and, therefore, is vital for understanding auditory perception.