Cellular mechanisms of oxygen and acid sensing in arterial chemoreceptors
Arterial chemoreceptors are an integral part of vital homeostatic mechanisms controlling both breathing and the cardiovascular system. They measure oxygen, carbon dioxide and pH levels in the blood and relay this information to respiratory and cardiovascular control centres in the brainstem. One example of their functional role is the classical reflex increase in breathing that occurs when we enter a low oxygen environment, such as occurs at altitude. Recent studies have also implicated them in the aetiology of some forms of hypertension.
Our research is primarily focussed upon understanding how these organs sense hypoxia, hypercapnia and acidosis. We work on the carotid body which is the main arterial chemoreceptor. These organs comprise of clusters of sensory cells called glomus or type-1 cells which form synapses with afferent nerve fibres from the carotid sinus nerve. This forms the basic sensory unit or glomerulus which is surrounded by glial like support cells (the type-2 or sustentacular cell) and the whole organ is richly vascularised.
Most of our research focusses upon the type-1 cell, which responds to chemostimuli with the secretion of various neurotransmitters. Type-1 cells are thus considered to be the primary site of chemotransduction. Our research is currently focussed upon a number of key elements in the sensory transduction process.
Calcium signalling. The proximal stimulus to neurosecretion in response to hypoxia etc. is an elevation in cytosolic calcium through voltage gated calcium entry. Regulation of calcium signalling is a key mechanism by which chemoreceptor output can be modulated.
Electrical signalling and ion channels. Calcium signalling (above) is driven by an electrical signalling process in which hypoxia and acidosis promote type-1 cell-membrane depolarisation leading to the initiation of action potentials. We are interested in characterising ion channels involved in this process and their modulation by chemostimuli. One of the key events in chemotransduction appears to be the inhibition of a background potassium channel by hypoxia and acidosis which initiates cell depolarisation. We have recently identified this channel as a heterodimer of TASK-1 and TASK-3 (kcnk3 & kcnk9 members of the tandem-p-domain K-channel family).
The molecular nature of the oxygen sensor. Whilst the effects of acidic stimuli may be directly transduced by acid sensing ion channels (e.g. TASK), the oxygen sensor is probably remote from the channel pore forming subunits. We are investigating a number of hypotheses regarding putative oxygen sensors/signalling pathways including the generation of gaseous signalling molecules (e.g. CO NO & H2S), reactive oxygen species, and metabolic pathways (see below).
Mitochondrial function. One of the most enduring theories regarding oxygen sensing in the carotid body is that it is linked to mitochondrial function. Numerous studies have shown that the carotid body can be powerfully excited by inhibitors of oxidative phosphorylation. A striking, and thus far seemingly unique, feature of mitochondrial function in these cells is that it is much (10-100 times) more sensitive to changes in the level of oxygen than are the mitochondria of other cells. We are therefore trying to identify the basis of what may be a functional adaptation of type-1 cell mitochondria to a role in oxygen sensing.
Effects of chronic hypoxia. During prolonged (days) exposure to hypoxia the oxygen sensitivity of the carotid body increases. This augments the drive to breath even further. This is part of the normal process of acclimatisation to altitude. Recent evidence suggests that, like the increase in haematocrit that occurs under these conditions, ventilatory acclimatisation to hypoxia/altitude is mediated by the HIF signalling system (an oxygen sensing pathway that controls gene transcription). We are currently investigating the role of HIF in regulating carotid body and type-1 cell function in collaboration with Profs Ratcliffe, Pugh & Robbins.
Effects of general anaesthetics. Most general anaesthetics have a depressive effect upon breathing. Inhalational anaesthetics in particular often powerfully inhibit ventilatory responses to hypoxia even at sub-clinical levels. In collaboration with Prof Panditt we are investigating the mechanisms by which general anaesthetics influence oxygen sensing in peripheral chemoreceptors.
In addition to our work on chemoreceptors the group also has an interest in the effects of hypoxia and acidosis on other tissues particularly the autonomic nervous system including sensory and sympathetic neurons.