Key result
Oxidative stress displaces EB1 from microtubule plus ends, which limits the forward trafficking of connexin 43 to the plasma membrane and reduces cell-cell electrical coupling.
Oxidative stress disrupts the microtubule-based forward delivery of connexin 43 by displacing EB1, leading to reduced gap junction coupling and slowed cardiac conduction.
May impair conduction in oxidative cardiac conditions; extends microtubule trafficking mechanisms but leaves open human validation.
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.
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Smyth et al. (2010) studied Ischemic cardiomyopathy and oxidative stress. Oxidative stress (H2O2 or ischemia-reperfusion) vs. Control conditions was evaluated on Connexin 43 localization at the intercalated disc and gap junction coupling. Oxidative stress displaces EB1 from microtubule plus ends, which limits the forward trafficking of connexin 43 to the plasma membrane and reduces cell-cell electrical coupling.
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