S 10 Cellular mechanisms of O 2 sensing : the carotid body as combined O 2 and glucose sensor
نویسندگان
چکیده
Oxygen sensing is part of the homeostatic biological processes necessary for adaptation of living organisms to variable habitats and physiologic situations. Cellular responses to hypoxia can be acute or chronic. Acute responses depend mainly on O2regulated ion channels which mediate adaptive changes in cell excitability, contractility and secretory activity. The main O2 sensor mediating the acute responses to hypoxia is the carotid body, a minute bilateral organ located in the bifurcation of the carotid artery, which contains afferent nerve fibres that activate the brainstem respiratory centres to produce hyperventilation. Stimulation of the carotid body is also known to produce sympathetic activation and this organ has been postulated to be involved in glucose control (Alvarez-Buylla & de Alvarez-Buylla, 1988). The O2-sensitive elements in the carotid body are the neuroectodermal-derived glomus cells. These are electrically excitable and have O2-regulated K + channels in their plasma membrane. Hypoxia signalling in glomus cells involves inhibition of K channels of the plasma membrane leading to cell depolarization, external Ca influx, and activation of neurotransmitter release, which, in turn, stimulates the afferent sensory fibers (for review, see López-Barneo et al. 2001). Despite the progress in the understanding of glomus cell electrophysiology and responsiveness to hypoxia, the molecular nature of the O2 sensor remains unknown. We have developed a carotid body thin slice preparation in which the response of glomus cells to low PO2 can be studied in almost optimal physiological conditions (Pardal et al. 2000). Using this technique we have investigated whether sensitivity of intact glomus cells to hypoxia is altered by mitochondrial electron transport chain (ETC) inhibition. We have also studied whether glomus cells participate in blood glucose detection. The results indicate that, as hypoxia, mitochondrial ETC inhibitors evoke an extracellular Cadependent secretory response from glomus cells. Sensitivity to lowering PO2 is not altered by blockade of mitochondrial electron flow in complexes I to IV, although responsiveness to hypoxia is selectively abolished by rotenone. Thus the data suggest that a rotenone binding protein is part of the O2 sensor. In addition, we have observed that low glucose increases secretion from intact single glomus cells in a graded manner, and that this response depends on extracellular Ca influx and requires glucose metabolism but not changes in intracellular ATP (Pardal & López-Barneo, 2002). Inhibition of voltage-gated K channels is the primary response to falling extracellular glucose, but sensitivity to low glucose is not altered by rotenone. Low glucose and hypoxia converge to raise cytosolic [Ca] in glomus cells and to release transmitters, which stimulate afferent sensory fibres and evoke sympathoadrenal activation. The function of glomus cells as combined O2 and glucose sensors, in which the two stimuli potentiate each other, is surely advantageous to facilitate activation of the counterregulatory measures in response to small reductions of any of the regulated variables.
منابع مشابه
K(+) channels in O(2) sensing and postnatal development of carotid body glomus cell response to hypoxia.
The sensitivity of carotid body chemoreceptors to hypoxia is low just after birth and increases over the first few weeks of the postnatal period. At present, it is believed that the hypoxia-induced excitation of carotid body glomus cells begins with the inhibition of the outward K(+) current via one or more O(2) sensors. Although the nature of the O(2) sensors and their signals that inhibit the...
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