Abstract
Specialized O2-sensing cells exhibit a particularly low threshold to regulation by O2 supply and function to maintain arterial pO2 within physiological limits. For example, hypoxic pulmonary vasoconstriction optimizes ventilation-perfusion matching in the lung, whereas carotid body excitation elicits corrective cardio-respiratory reflexes. It is generally accepted that relatively mild hypoxia inhibits mitochondrial oxidative phosphorylation in O2-sensing cells, thereby mediating, in part, cell activation. However, the mechanism by which this process couples to Ca2+ signaling mechanisms remains elusive, and investigation of previous hypotheses has generated contrary data and failed to unite the field. We propose that a rise in the cellular AMP/ATP ratio activates AMP-activated protein kinase and thereby evokes Ca2+ signals in O2-sensing cells. Co-immunoprecipitation identified three possible AMP-activated protein kinase subunit isoform combinations in pulmonary arterial myocytes, with alpha1 beta2 gamma1 predominant. Furthermore, their tissue-specific distribution suggested that the AMP-activated protein kinase-alpha1 catalytic isoform may contribute, via amplification of the metabolic signal, to the pulmonary selectivity required for hypoxic pulmonary vasoconstriction. Immunocytochemistry showed AMP-activated protein kinase-alpha1 to be located throughout the cytoplasm of pulmonary arterial myocytes. In contrast, it was targeted to the plasma membrane in carotid body glomus cells. Consistent with these observations and the effects of hypoxia, stimulation of AMP-activated protein kinase by phenformin or 5-aminoimidazole-4-carboxamide-riboside elicited discrete Ca2+ signaling mechanisms in each cell type, namely cyclic ADP-ribose-dependent Ca2+ mobilization from the sarcoplasmic reticulum via ryanodine receptors in pulmonary arterial myocytes and transmembrane Ca2+ influx into carotid body glomus cells. Thus, metabolic sensing by AMP-activated protein kinase may mediate chemotransduction by hypoxia.
Highlights
Specialized O2-sensing cells exhibit a low threshold to regulation by O2 supply and function to maintain arterial pO2 within physiological limits
They did not cross-react with anti-␣1 or -␣2 antibodies, and immunoprecipitate kinase assays revealed that ␥2 accounted for 40% and ␥1 for 60% of the total AMPK activity in pulmonary arterial smooth muscle lysates, with ␥3 accounting for an insignificant fraction (n ϭ 3, 32 arteries, 8 animals) (Fig. 1B)
Our findings suggest that this leads to a rise in the cellular AMP/ATP ratio, consequent AMPK activation, and the initiation of cell-specific Ca2ϩ signaling mechanisms in pulmonary arterial smooth muscle and carotid body glomus cells (Fig. 4E)
Summary
Specialized O2-sensing cells exhibit a low threshold to regulation by O2 supply and function to maintain arterial pO2 within physiological limits. Specialized O2-sensing cells within the body have evolved as vital homeostatic mechanisms that monitor O2 supply and alter respiratory and circulatory function, as well as the capacity of the blood to transport O2 By these means, arterial pO2 is maintained within physiological limits. O2-sensitive mechanisms independent of mitochondria may play a role [3,4,5], it is generally accepted that relatively mild hypoxia inhibits mitochondrial oxidative phosphorylation and that this underpins, at least in part, cell activation (2, 6 –10). Given that inhibition of mitochondrial oxidative phosphorylation by hypoxia would be expected to promote a rise in the AMP/ATP ratio [20], we considered the proposal [31] that AMPK activation may mediate, in part, pulmonary artery constriction and carotid body excitation by hypoxia.
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