Abstract
The carotid body (CB) is a key chemoreceptor organ in which glomus cells sense changes in blood O2, CO2, and pH levels. CB glomus cells have also been found to detect hypoglycemia in both non-primate mammals and humans. O2 and low-glucose responses share a common final pathway involving membrane depolarization, extracellular calcium influx, increase in cytosolic calcium concentration, and neurotransmitter secretion, which stimulates afferent sensory fibers to evoke sympathoadrenal activation. On the other hand, hypoxia and low glucose induce separate signal transduction pathways. Unlike O2 sensing, the response of the CB to low glucose is not altered by rotenone, with the low glucose-activated background cationic current unaffected by hypoxia. Responses of the CB to hypoglycemia and hypoxia can be potentiated by each other. The counter-regulatory response to hypoglycemia by the CB is essential for the brain, an organ that is particularly sensitive to low glucose. CB glucose sensing could be altered in diabetic patients, particularly those under insulin treatment, as well as in other medical conditions such as sleep apnea or obstructive pulmonary diseases, where chronic hypoxemia presents with plastic modifications in CB structure and function. The current review will focus on the following main aspects: (1) the CB as a low glucose sensor in both in vitro and in vivo models; (2) molecular and ionic mechanisms of low glucose sensing by glomus cells, (3) the interplay between low glucose and O2 sensing in CB, and (4) the role of CB low glucose sensing in the pathophysiology of cardiorespiratory and metabolic diseases, and how this may serve as a potential therapeutic target.
Highlights
Hypoglycemia, or a low blood glucose level, is a physiological condition that is detected by the body to trigger compensatory counter-regulatory responses, which are essential for maintaining glucose supply to organs, such as the brain, strictly dependent on this metabolite for survival
In our initial study we reported that, like O2 sensing by the carotid body (CB), macroscopic voltage-gated outward K+ currents are inhibited in patch-clamped rat glomus cells exposed to glucose-free solutions (Pardal and Lopez-Barneo, 2002b)
The secretory response to low glucose increases in the presence of low PO2 in rat CB slices (Pardal and Lopez-Barneo, 2002b), and we have recently shown that glomus cells in the human CB are glucose sensors and show the same responses, as described in lower mammals (Figures 3A–D)
Summary
Hypoglycemia, or a low blood glucose level, is a physiological condition that is detected by the body to trigger compensatory counter-regulatory responses, which are essential for maintaining glucose supply to organs, such as the brain, strictly dependent on this metabolite for survival. O2-sensitive K+ channels are closed in the plasma membrane of glomus cells, which triggers membrane depolarization, Ca2+ influx, and neurotransmitter release. This signal is sent to the brainstem respiratory centers by afferent www.frontiersin.org. Carotid body glucose sensing and disease fibers of the carotid-sinus nerve to mediate a compensatory acute hyperventilatory response in order to increase O2 tension in the blood (Weir et al, 2005; Lopez-Barneo et al, 2008). Besides the CB glomus cells, O2-sensitive ion channels have been described in numerous cell classes, such as chromaffin cells in the adrenal medulla, neuroepithelial bodies of the lung, pulmonary and systemic vascular smooth muscle, and heart myocytes among others (see for review Lopez-Barneo et al, 1999, 2001)
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