Carotid body chemoreceptor activity in mice deficient in selected subunits of NADPH oxidase.

Exposure of the carotid body to hypoxia elicits increased neural activity in the carotid sinus nerve (CSN), and reflex cardio-pulmonary adjustments which mitigate the adverse effects of hypoxemia. Increased carotid body activity occurs at relatively moderate arterial P02, in contrast to the severe hypoxia required to elicit metabolic and functional adjustments in non-02 sensing tissues (S.J.Fidone et al. 1997). Chemosensory type I cells derived from neuroectoderm are responsible for this exquisite sensitivity, and numerous laboratories have reported that low P02 inhibits the conductance of a variety of voltage sensitive and voltage-insensitive K+-channels in these cells. Yet the molecular mechanism underlying the P02 modulation of cell currents remains uncertain and controversial (H.Acker et al 1994, A.M.Riesco-Fagundo et al2001). Various heme proteins have been proposed as primary O2 sensors, and one set of data in particular suggests the involvement of a multi-component cytochrome b-containing NADPH oxidase which may be similar if not identical to the superoxide generating enzyme commonly found in phagocytic cells (H.Acker et al. 1994) (H.Acker et al. 1994), but the relationship between PO2 and ROS levels in type I cells has not been firmly established. In other cells and tissues hypoxia can increase or decrease ROS production in either mitochondria or via NADPH oxidase (I.O’Kelly et al. 2000, G.B Waypa et al. 2001). In addition, the target of ROS in type I cells is an unknown and critical factor in determining the effect of NADPH oxidase on cell activity. Recent studies have indicated that voltage-sensitive K+-channels in type I cells are modulated by hypoxia via a mechanism independent of soluble factors such as ROS (A.M. Riesco-Fagundo et al. 2001). Thus ROS do not appear to be necessary for cell activation. On the other hand, if hypoxia enhances NADPH oxidase activity, elevated ROS levels may increase the open probability of K+-channels thus facilitating cell repolarization. Such a scheme is consistent with elevated CSN activity in p47phox-gene deleted animals. Clarification of these issues must await future measurements of the effect of hypoxia on NADPH oxidase activity, and evaluation of the interaction of ROS with the chemotransduction machinery in type I cells.