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    ABSTRACT: In the myometrium SR Ca(2+) depletion promotes an increase in force but unlike several other smooth muscles, there is no Ca(2+) sparks-STOCs coupling mechanism to explain this. Given the importance of the control of contractility for successful parturition, we have examined, in pregnant rat myometrium, the effects of SR Ca(2+)-ATPase (SERCA) inhibition on the temporal relationship between action potentials, Ca(2+) transients and force. Simultaneous recording of electrical activity, calcium and force showed that SERCA inhibition, by cyclopiazonic acid (CPA 20μM), caused time-dependent changes in excitability, most noticeably depolarization and elevations of baseline [Ca(2+)]i and force. At the onset of these changes there was a prolongation of the bursts of action potentials and a corresponding series of Ca(2+) spikes, which increased the amplitude and duration of contractions. As the rise of baseline Ca(2+) and depolarization continued a point was reached when electrical and Ca(2+) spikes and phasic contractions ceased, and a maintained, tonic force and Ca(2+) was produced. Lanthanum, a non-selective blocker of store-operated Ca(2+) entry, but not the L-type Ca(2+) channel blocker nifedipine (1-10μM), could abolish the maintained force and calcium. Application of the agonist, carbachol, produced similar effects to CPA, i.e. depolarization, elevation of force and calcium. A brief, high concentration of carbachol, to cause SR Ca(2+) depletion without eliciting receptor-operated channel opening, also produced these results. The data obtained suggest that in pregnant rats SR Ca(2+) release is coupled to marked Ca(2+) entry, via store operated Ca(2+) channels, leading to depolarization and enhanced electrical and mechanical activity.
    Full-text · Article · Sep 2014 · Cell Calcium
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    ABSTRACT: Ubiquitin, a 76 amino-acid polypeptide, presents a compact three-dimensional structure, utilising a fold that recurs within larger polypeptides and in other protein modifiers, such as NEDD8 and SUMO. Ubiquitylation was initially recognised as a signal for proteasome-mediated degradation. We shall consider here how this view has evolved to appreciate that the dynamic appendage of different types of ubiquitin chains represents a versatile, three-dimensional code, fundamental to the control of many cellular processes.
    Full-text · Article · Mar 2014 · Current biology: CB
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    ABSTRACT: Little is known about how hypercholesterolemia affects Ca2+ signalling in the vasculature of ApoE−/− mice, a model of atherosclerosis. Our objectives were therefore to determine (i) if hypercholesterolemia alters Ca2+ signalling in aortic endothelial cells before overt atherosclerotic lesions occur, (ii) how Ca2+ signals are affected in older plaque-containing mice, and (iii) whether Ca2+ signalling changes were translated into contractility differences. Using confocal microscopy we found agonist-specific Ca2+ changes in endothelial cells. ATP responses were unchanged in ApoE−/− cells and methyl-β-cyclodextrin, which lowers cholesterol, was without effect. In contrast, Ca2+ signals to carbachol were significantly increased in ApoE−/− cells, an effect methyl-β-cyclodextrin reversed. Ca2+ signals were more oscillatory and store-operated Ca2+ entry decreased as mice aged and plaques formed. Despite clearly increased Ca2+ signals, aortic rings pre-contracted with phenylephrine had impaired relaxation to carbachol. This functional deficit increased with age, was not related to ROS generation, and could be partially rescued by methyl-β-cyclodextrin. In conclusion, carbachol-induced calcium signalling and handling are significantly altered in endothelial cells of ApoE−/− mice before plaque development. We speculate that reduction in store-operated Ca2+ entry may result in less efficient activation of eNOS and thus explain the reduced relaxatory response to CCh, despite the enhanced Ca2+ response.
    Full-text · Article · Mar 2014 · Cell calcium
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