All animal life requires oxygen to survive, but how does an organism know if it is getting enough and what happens when it isn’t?  This group’s work focuses upon two aspects of oxygen physiology, the sensory mechanisms by which the body monitors acute changes in oxygen supply or utilisation, and the pathophysiology of tissue anoxia.

Current Research Programme

Chemoreception

In vertebrates, the provision of oxygen to tissues depends upon the cardiovascular and respiratory systems.  The efficient functioning of these systems is ensured by complex regulatory mechanisms which rely upon sensory information regarding the levels of both arterial oxygen and a key metabolite of aerobic respiration carbon dioxide (which forms carbonic acid).  Blood oxygen, CO₂ and pH levels are continuously monitored by central and peripheral chemoreceptors, which evoke respiratory and cardiovascular reflexes.  Despite the fundamental importance of these sensory functions, the mechanisms by which chemoreceptors detect oxygen and CO₂ are still poorly understood.  One of the primary research objectives of this laboratory is to elucidate the mechanisms responsible for oxygen, CO₂ and acid sensing in peripheral chemoreceptors.

The peripheral chemoreceptors play a vital role in initiating a number of protective responses to hypoxemia and acidosis.  The most well known reflex is an increase in ventilation; but these receptors also initiate reflex modulation of regional blood flow, cardiac output and catecholamine secretion.  Within the carotid body the primary receptor is the type-1 cell.  Type-1 cells respond to chemostimuli (either hypoxia or acidosis) with a rise in intracellular calcium; this causes neurosecretion which leads to excitation of afferent nerves which project to respiratory and cardiovascular control centres in the brain stem.  Our study of chemoreception in this organ has therefore focussed upon identifying the mechanisms of excitation secretion coupling and calcium signalling in the type-1 cell.

Over the past decade we have shown that type-1 cells respond to hypoxia with a membrane depolarisation followed by voltage-gated calcium entry.  This depolarisation is caused primarily through the inhibition of a novel TASK-like background potassium channel.  Recent studies from our laboratory indicate that this channel is exquisitely sensitive to the inhibition of oxidative metabolism and is directly stimulated by cytosolic ATP, suggesting that it may be a member of a new class of ATP regulated ion channels.  Our current research therefore focuses upon further characterising this channel, determining the mechanisms by which ATP regulates channel activity and evaluating a potential role for the mitochondrion in oxygen sensing.

Ischemia and Cardiac Nerves

Understanding the cellular events underlying cardiac dysfunction during myocardial ischemia is fundamental to the development of therapeutic or protective strategies.  Whilst much research has focussed upon the cardiac myocyte, other cell types can also play an important role in determining the outcome of an ischemic episode. 

The release of catecholamines is a key event in myocardial ischemia that results in a substantial (micromolar) increase in noradrenaline levels within the ischemic zone. This massive accumulation of noradrenaline is potentially deleterious because i) it increases energy demand leading to exacerbation of myocardial hypoxia and ATP depletion; and ii) it stimulates myocyte Ca²⁺-channels and SR-Ca²⁺-ATPases thus promoting Ca²⁺-overload which can cause arrhythmias. 

Despite the potential importance of noradrenaline release during ischemia there have been few investigations into the mechanisms by which this release occurs.  What is clear, however, is that this occurs even in isolated hearts; thus ischemia-evoked noradrenaline release is a locally mediated event.  Our research is aimed at elucidating the signalling pathways involved in mediating this noradrenaline release in response to ischemia.

Technical aspects

A large part of the group’s research involves the study of the effects of hypoxia and acidosis upon cell signalling.  The technical approaches used include fluorescent probes and imaging techniques to study intracellular ion homeostasis (pH, calcium and sodium) and mitochondrial function, and electrophysiological techniques (patch clamp) to study ion channel function.

Further information can be found at: http://www.physiol.ox.ac.uk/~kjb/

Keith Buckler