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Limited forward trafficking of connexin 43 reduces cell-cell coupling in stressed human and mouse myocardium
James W. Smyth, … , Neil C. Chi, Robin M. Shaw
James W. Smyth, … , Neil C. Chi, Robin M. Shaw
Published December 28, 2009
Citation Information: J Clin Invest. 2010;120(1):266-279. https://doi.org/10.1172/JCI39740.
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Research Article Article has an altmetric score of 1

Limited forward trafficking of connexin 43 reduces cell-cell coupling in stressed human and mouse myocardium

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Abstract

Gap junctions form electrical conduits between adjacent myocardial cells, permitting rapid spatial passage of the excitation current essential to each heartbeat. Arrhythmogenic decreases in gap junction coupling are a characteristic of stressed, failing, and aging myocardium, but the mechanisms of decreased coupling are poorly understood. We previously found that microtubules bearing gap junction hemichannels (connexons) can deliver their cargo directly to adherens junctions. The specificity of this delivery requires the microtubule plus-end tracking protein EB1. We performed this study to investigate the hypothesis that the oxidative stress that accompanies acute and chronic ischemic disease perturbs connexon forward trafficking. We found that EB1 was displaced in ischemic human hearts, stressed mouse hearts, and isolated cells subjected to oxidative stress. As a result, we observed limited microtubule interaction with adherens junctions at intercalated discs and reduced connexon delivery and gap junction coupling. A point mutation within the tubulin-binding domain of EB1 reproduced EB1 displacement and diminished connexon delivery, confirming that EB1 displacement can limit gap junction coupling. In zebrafish hearts, oxidative stress also reduced the membrane localization of connexin and slowed the spatial spread of excitation. We anticipate that protecting the microtubule-based forward delivery apparatus of connexons could improve cell-cell coupling and reduce ischemia-related cardiac arrhythmias.

Authors

James W. Smyth, Ting-Ting Hong, Danchen Gao, Jacob M. Vogan, Brian C. Jensen, Tina S. Fong, Paul C. Simpson, Didier Y.R. Stainier, Neil C. Chi, Robin M. Shaw

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Figure 4

Microtubule dynamics are decreased and fewer microtubules approach the cell cortex during oxidative stress.

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Microtubule dynamics are decreased and fewer microtubules approach the c...
HeLa cells were transfected with α-tubulin–EGFP and visualized by spinning-disk confocal microscopy to capture 5-minute time courses 18 hours after transfection. When appropriate, H2O2 was added to a final concentration of 200 μM 45 minutes prior to imaging. (A) Individual microtubules were tracked using ImageJ and the MTrackJ plug-in. Red arrowheads represent a static point of reference; black arrowheads represent a dynamic microtubule plus end. (B) Quantification of microtubule growth rate. (C) Arrows point to microtubules approaching cell cortex during a 5-minute acquisition time. Graph illustrates quantification of the numbers of microtubules approaching the cell cortex/10 μm membrane. Original magnification, ×100. Scale bars: 10 μm. Results are representative of 3 separate experiments. Statistical analysis was performed using the Student’s unpaired t test. Values represent mean ± SEM. ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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