Hypoxic regulation of ion channel function and expression

Acute hypoxia regulates the activity of specific ion channels in a rapid and reversible manner. Such effects underlie appropriate cellular responses to hypoxia which are designed to initiate cardiorespiratory reflexes and contribute importantly to other tissue responses, all of which are designed to improve tissue O2 supply. These responses include excitation of chemoreceptors as well as pulmonary vasoconstriction and systemic vasodilatation. However, such responses may also contribute to the adverse responses to hypoxia, such as excitotoxicity in the central nervous system. Whilst numerous ion channel types are known to be modulated by acute hypoxia, the nature of the O2 sensor in most tissues remains to be identified. Prolonged (chronic) hypoxia regulates functional expression of ion channels, and so remodels excitability of various cell types. Whilst this may contribute to adaptive responses such as high-altitude acclimatization, such altered channel expression may also contribute to the onset of pathological disorders, including Alzheimer's disease. Indeed, evidence is emerging that production of pathological peptides associated with Alzheimer's disease is increased during prolonged hypoxia. Such effects may account for the known increased incidence of this disease in patients who have previously endured hypoxic episodes, such as congestive heart failure and stroke. Identification of the mechanisms coupling hypoxia to the increased production of these peptides is likely to be of therapeutic benefit

Interactions of chemostimuli at the single cell level: studies in a model system

The responses of afferent chemosensory fibres of the carotid body to individual chemostimuli have long been established. However, the mechanisms underlying the multiplicative interactions of these stimuli (i.e. how the combined effects of hypoxia and hypercapnia exert a greater effect on afferent nerve discharge than the sum of their individual effects) have not been elucidated. Using the membrane hypothesis for carotid body chemoreception, in which chemostimuli inhibit type I cell K+ channels, leading to depolarization, voltage-gated Ca2+ entry and hence the triggering of exocytosis, this article considers data acquired in isolated type I carotid body cells and model chemoreceptor (PC12) cells to attempt to explain stimulus interactions. Whilst stimulus interactions are not clearly evident at the level of K+ channel inhibition or rises of [Ca2+](i), they are apparent at the level of transmitter release. Thus, it is clear that individual chemoreceptor cells can sense multiple stimuli, and that interactions of these stimuli can produce greater than additive effects in terms of transmitter release

Beware of Courts Bearing Gifts: Transparency and the Court of Justice of the European Union

This article reconsiders the principle of transparency in the European Union (EU) legal order and takes as its focal point the contribution of the EU Courts as regards the presumptions of non-disclosure of EU documents. The aim is to investigate the role played by the judiciary in relation to a twofold question: How open can the Union’s decision-making be, and is it possible for citizens to participate in the decision-making process of EU institutions, bodies, offices and agencies? The article argues that accountability deficits in the field of access to documents have been filled, to an extent, by the EU Courts’ imposition of boundaries on the broad derogations to the right of access to documents. But nevertheless, the article concludes that the establishment through the case law of general presumptions against openness has fundamentally weakened the standards of accountability. Rather regrettably, although the EU legislature set the default position to the widest access to documents, this has been reversed to non-disclosure by the EU judiciary as regards non-legislative documents

Acute oxygen sensing: diverse but convergent mechanisms in airway and arterial chemoreceptors

Airway neuroepithelial bodies sense changes in inspired O2, whereas arterial O2 levels are monitored primarily by the carotid body. Both respond to hypoxia by initiating corrective cardiorespiratory reflexes, thereby optimising gas exchange in the face of a potentially deleterious O2 supply. One unifying theme underpinning chemotransduction in these tissues is K+ channel inhibition. However, the transduction components, from O2 sensor to K+ channel, display considerable tissue specificity yet result in analogous end points. Here we highlight how emerging data are contributing to a more complete understanding of O2 chemosensing at the molecular level

Irregular Migrants: Can Humane Treatment be Balanced against Efficient Removal?

The controversial Returns Directive has now been the subject of considerable jurisprudence of the CJEU, addressing many important issues of interpretation. This paper assesses whether the CJEU has been successful in its apparent attempts to balance humanitarian concerns with the EU legislator’s apparent objective of removing irregular migrants from the territory as quickly as possible

The Commonwealth and the EU: let’s do (trade with) both

The Leave campaign argues that quitting the Union would enable Britain to negotiate free trade agreements with more Commonwealth countries. Steve Peers says it certainly could – although the EU already has, or is negotiating, FTAs with most Commonwealth states – but they probably wouldn’t compensate for the loss of free trade with the EU