Role of calcium in the activation of endothelial cells

The involvement of calcium in the release of EDRF from cultured endothelial cells is reviewed. It is suggested that both intracellular and extracellular calcium can release EDRF depending not only on the experimental conditions but also on the agonist involved in the release. Calcium enters the cell, following receptor occupation, through a nonselective receptor-operated channel. Intracellular release of calcium following receptor occupation is probably via the production of inositol trisphosphate (IP3). It is suggested that the initial calcium signal for the release of endothelium-derived relaxant factor (EDRF) is of intracellular origin whereas the maintained release of EDRF is due to calcium entry from the extracellular space

Calcium entry through receptor-operated channels in bovine pulmonary artery endothelial cells

The activation of endothelial cells by endothelium-dependent vasodilators has been investigated using bioassay, patch clamp and 45Ca flux methods. Cultured pulmonary artery endothelial cells have been demonstrated to release EDRF in response to thrombin, bradykinin, ATP and the calcium ionophore A23187. The resting membrane potential of the endothelial cells was -56 mV and the cells were depolarized by increasing extracellular K+ or by the addition of (0.1-1.0 mM) Ba2+ to the bathing solution. The electrophysiological properties of the cultured endothelial cells suggest that the membrane potential is maintained by an inward rectifying K+ channel with a mean single channel conductance of 35.6 pS. The absence of a depolarizationactivated inward current and the reduction of 45Ca influx with high K+ solution suggests that there are no functional voltage-dependent calcium or sodium channels. Thrombin and bradykinin were shown to evoke not only an inward current (carried by Na+ and Ca2+) but also an increase in 45Ca influx suggesting that the increase in intracellular calcium necessary for EDRF release is mediated by an opening of a receptor operated channel. High doses of thrombin and bradykinin induced intracellular calcium release, however, at low doses of thrombin no intracelluar calcium release was observed. We propose that the increased cytosolic calcium concentration in endothelial cells induced by endothelium dependent vasodilators is due to the influx of Ca2+ through a receptor operated ion channel and to a lesser degree to intracellular release of calcium from a yet undefined intracellular store. 1987

Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice

Although Parkinson's disease (PD) is characterized primarily by loss of nigrostriatal dopaminergic neurons, there is a concomitant loss of norepinephrine (NE) neurons in the locus coeruleus. Dopaminergic lesions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are commonly used to model PD, and although MPTP effectively mimics the dopaminergic neuropathology of PD in mice, it fails to produce PD-like motor deficits. We hypothesized that MPTP is unable to recapitulate the motor abnormalities of PD either because the behavioral paradigms used to measure coordinated behavior in mice are not sensitive enough or because MPTP in the absence of NE loss is insufficient to impair motor control. We tested both possibilities by developing a battery of coordinated movement tests and examining motor deficits in dopamine β-hydroxylase knockout (Dbh−/−) mice that lack NE altogether. We detected no motor abnormalities in MPTP-treated control mice, despite an 80% loss of striatal dopamine (DA) terminals. Dbh−/− mice, on the other hand, were impaired in most tests and also displayed spontaneous dyskinesias, despite their normal striatal DA content. A subset of these impairments was recapitulated in control mice with 80% NE lesions and reversed in Dbh−/− mice, either by restoration of NE or treatment with a DA agonist. MPTP did not exacerbate baseline motor deficits in Dbh−/− mice. Finally, striatal levels of phospho-ERK-1/2 and ΔFosB/FosB, proteins which are associated with PD and dyskinesias, were elevated in Dbh−/− mice. These results suggest that loss of locus coeruleus neurons contributes to motor dysfunction in PD

Proceedings of the 4th World Conference on Research Integrity

CITATION: O’Brien, S. P., et al. 2016. Proceedings of the 4th World Conference on Research Integrity. Research Integrity and Peer Review, 1:9, doi:10.1186/s41073-016-0012-9.The original publication is available at https://researchintegrityjournal.biomedcentral.comThese Proceedings contain the abstracts of the presentations given at the 4th World Conference in concurrent sessions, partner symposia, and poster sessions. Also included are summaries of the discussions in three focus tracks, which allowed delegates to consider and work on questions about the roles of funders, institutions, and countries in improving research systems and strengthening research integrity. Videos of the plenary presentations are available at the conference website (www.wcri2015.org).https://researchintegrityjournal.biomedcentral.com/articles/10.1186/s41073-016-0012-