α-Haemoglobin regulates sympathoadrenal cell metabolism to maintain a catecholaminergic phenotype.

Discovery of haemoglobin A expression outside of the erythroid cell lineage suggests that oxygen transport is the main, but not the unique, function of adult haemoglobin chains in mammals. The contribution of haemoglobin A to antioxidant defences has been proposed in the territories where it is expressed. Catecholaminergic cells rely on an active oxidative metabolism to accomplish their biological function, but are exposed to strong oxidative stress due to metabolism of catecholaminergic transmitters. We show in the present study that peripheral catecholaminegic cells express the α- and not the ß-haemoglobin A chains, and that α-haemoglobin expression could modulate the antioxidant capabilities of these cells. We also show that α-haemoglobin overexpression in PC12 cells leads to a selective increase of tyrosine hydroxylase synthesis and activity. This is achieved by means of a reorganization of antioxidant defences, decreasing cytoplasmic glutathione peroxidase and superoxide dismutase, and increasing mitochondrial peroxidase. Moreover, α-haemoglobin induces a decrease in lipogenesis and increase in lipid degradation, situations that help save NAD(P)H and favour supply of acetyl-CoA to the tricarboxylic acid cycle and production of reducing equivalents in the cell. All of these results point to a role for α-haemoglobin as a regulator of catecholaminergic cell metabolism required for phenotype acquisition and maintenance.

Carotid body chemosensory responses in mice deficient of TASK channels.

Background K(+) channels of the TASK family are believed to participate in sensory transduction by chemoreceptor (glomus) cells of the carotid body (CB). However, studies on the systemic CB-mediated ventilatory response to hypoxia and hypercapnia in TASK1- and/or TASK3-deficient mice have yielded conflicting results. We have characterized the glomus cell phenotype of TASK-null mice and studied the responses of individual cells to hypoxia and other chemical stimuli. CB morphology and glomus cell size were normal in wild-type as well as in TASK1(-/-) or double TASK1/3(-/-) mice. Patch-clamped TASK1/3-null glomus cells had significantly higher membrane resistance and less hyperpolarized resting potential than their wild-type counterpart. These electrical parameters were practically normal in TASK1(-/-) cells. Sensitivity of background currents to changes of extracellular pH was drastically diminished in TASK1/3-null cells. In contrast with these observations, responsiveness to hypoxia or hypercapnia of either TASK1(-/-) or double TASK1/3(-/-) cells, as estimated by the amperometric measurement of catecholamine release, was apparently normal. TASK1/3 knockout cells showed an enhanced secretory rate in basal (normoxic) conditions compatible with their increased excitability. Responsiveness to hypoxia of TASK1/3-null cells was maintained after pharmacological blockade of maxi-K(+) channels. These data in the TASK-null mouse model indicate that TASK3 channels contribute to the background K(+) current in glomus cells and to their sensitivity to external pH. They also suggest that, although TASK1 channels might be dispensable for O(2)/CO(2) sensing in mouse CB cells, TASK3 channels (or TASK1/3 heteromers) could mediate hypoxic depolarization of normal glomus cells. The ability of TASK1/3(-/-) glomus cells to maintain a powerful response to hypoxia even after blockade of maxi-K(+) channels, suggests the existence of multiple sensor and/or effector mechanisms, which could confer upon the cells a high adaptability to maintain their chemosensory function.