Abstract
Carotid body glomus cells are multimodal arterial chemoreceptors able to sense and integrate changes in several physical and chemical parameters in the blood. These cells are also essential for O2 homeostasis. Glomus cells are prototypical peripheral O2 sensors necessary to detect hypoxemia and to elicit rapid compensatory responses (hyperventilation and sympathetic activation). The mechanisms underlying acute O2 sensing by glomus cells have been elusive. Using a combination of mouse genetics and single-cell optical and electrophysiological techniques, it has recently been shown that activation of glomus cells by hypoxia relies on the generation of mitochondrial signals (NADH and reactive oxygen species), which modulate membrane ion channels to induce depolarization, Ca2+ influx, and transmitter release. The special sensitivity of glomus cell mitochondria to changes in O2 tension is due to Hif2α-dependent expression of several atypical mitochondrial subunits, which are responsible for an accelerated oxidative metabolism and the strict dependence of mitochondrial complex IV activity on O2 availability. A mitochondrial-to-membrane signaling model of acute O2 sensing has been proposed, which explains existing data and provides a solid foundation for future experimental tests. This model has also unraveled new molecular targets for pharmacological modulation of carotid body activity potentially relevant in the treatment of highly prevalent medical conditions.
Highlights
Oxygen (O2) is essential for survival of mammalian cells due to its role in numerous biochemical reactions, in particular, in mitochondrial ATP synthesis by oxidative phosphorylation
The knowledge of carotid body (CB) physiology and the sensory function of glomus cells have steadily advanced in the last years
The molecular mechanisms underlying glomus cell acute responsiveness to hypoxia have remained elusive, the membrane signaling (MMS) model summarized in this paper has provided an unprecedented integrated view of glomus cell function that robustly explains most of the data available and, in addition, can be further tested experimentally
Summary
Oxygen (O2) is essential for survival of mammalian cells due to its role in numerous biochemical reactions, in particular, in mitochondrial ATP synthesis by oxidative phosphorylation. Among the several attractive hypotheses postulated are the involvement of a specific NADPH oxidase, activation of AMP kinase during hypoxia, the reversible fast regulation of ion channels by gasotransmitters such as carbon monoxide and hydrogen sulfide, or the expression of an atypical olfactory receptor (Olfr; see for recent reviews Lopez-Barneo et al, 2016; Rakoczy and Wyatt, 2018) All these processes can influence glomus cell function, none of them seem to be essential for acute O2 sensing because the various mouse models generated after ablation of the genes coding the relevant enzymes or receptors showed CB with practically normal responsiveness to hypoxia (He et al, 2002; Ortega-Saenz et al, 2006; Mahmoud et al, 2016; Wang et al, 2017; Torres-Torrelo et al, 2018). We discuss the potential medical implications of recent advances in CB research
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