The molecular underpinnings of the oxygen sensitivity of the carotid body Type I cells are becoming better defined as research begins to identify potential interactions between previously separate theories. Nevertheless, the field of oxygen chemoreception still presents the general observer with a bewildering array of potential signalling pathways by which a fall in oxygen levels might initiate Type I cell activation. The purpose of this brief review is to address five of the current oxygen sensing hypotheses: the lactate-Olfr 78 hypothesis of oxygen chemotransduction; the role mitochondrial ATP and metabolism may have in chemotransduction; the AMP-activated protein kinase hypothesis and its current role in oxygen sensing by the carotid body; reactive oxygen species as key transducers in the oxygen sensing cascade; and the mechanisms by which H S, reactive oxygen species and haem oxygenase may integrate to provide a rapid oxygen sensing transduction system. Over the previous 15 years several lines of research into acute hypoxic chemotransduction mechanisms have focused on the integration of mitochondrial and membrane signalling. This review places an emphasis on the subplasmalemmal-mitochondrial microenvironment in Type I cells and how theories of acute oxygen sensing are increasingly dependent on functional interaction within this microenvironment.

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The Carotid Bodies (CB) are peripheral chemoreceptors that detect changes in arterial oxygenation and, via afferent inputs to the brainstem, correct the pattern of breathing to restore blood gas homeostasis. Herein, preliminary evidence is presented supporting a novel oxygen-sensing hypothesis which suggests CB Type I cell “hypoxic signaling” may in part be mediated by mitochondria-generated thermal transients in TASK-channel-containing microdomains. Distances were measured between antibody-labeled mitochondria and TASK-potassium channels in primary rat CB Type I cells. Sub-micron distance measurements (TASK-1: 0.33 ± 0.04 µm, n = 47 vs TASK-3: 0.32 ± 0.03 µm, n = 54) provided evidence for CB Type I cell oxygen-sensing microdomains. A temperature-sensitive dye (ERthermAC) indicated that inhibition of mitochondrial activity in isolated cells caused a rapid and reversible inhibition of mitochondrial thermogenesis and thus temperature in these microdomains. Whole-cell perforated-patch current-clamp electrophysiological recordings demonstrated sensitivity of resting membrane potential (Vm) to temperature: lowering bath temperature from 37°C to 24°C induced consistent and reversible depolarizations (Vm at 37°C: 48.4 ± 4.11 mV vs 24°C: 31.0 ± 5.69 mV; n = 5; p < 0.01). These data suggest that hypoxic inhibition of mitochondrial thermogenesis may play an important role in oxygen chemotransduction in the CB. A reduction in temperature within cellular microdomains will inhibit plasma membrane ion channels, influence the balance of cellular phosphorylation–dephosphorylation, and may extend the half-life of reactive oxygen species. The characterization of a thermosensory chemotransduction mechanism, that may also be used by other oxygen-sensitive cell types and may impact multiple other chemotransduction mechanisms is critical if we are to fully understand how the CBs, and potentially other oxygen-sensitive cells, respond to hypoxia.

Objective The combination of opioids and ethanol can synergistically depress breathing and the acute ventilatory response to hypoxia. Multiple studies have shown that the underlying mechanisms for this may involve calcium channel inhibition in central neurons. But we have previously identified opioid receptors in the carotid bodies and shown that their activation inhibits calcium influx into the chemosensitive cells. Given that the carotid bodies contribute to the drive to breathe and underpin the acute hypoxic ventilatory response, we hypothesized that ethanol and opioids may act synergistically in these peripheral sensory organs to further inhibit calcium influx and therefore inhibit ventilation. Methods Carotid bodies were removed from 56 Sprague–Dawley rats (1021 days old) and then enzymatically dissociated to allow calcium imaging of isolated chemosensitive type I cells. Cells were stimulated with high K + in the presence and absence of the µ-opioid agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) (10 µM), a maximal sublethal concentration of ethanol (3 g L -1 , 65.1 mM) or a combination of both. Results DAMGO alone significantly inhibited Ca 2+ influx but this effect was not potentiated by the high concentration of ethanol. Conclusion These results indicate for the first time that while opioids may suppress breathing via an action at the level of the carotid bodies, ethanol is unlikely to potentiate inhibition via this pathway. Thus, the synergistic effects of ethanol and opioids on ventilatory parameters are likely mediated by central rather than peripheral actions.