Carotid body type I cells engage flavoprotein and Pin1 for oxygen sensing

Abstract

Carotid body (CB) type I cells sense the blood Po2 and generate a nervous signal for stimulating ventilation and circulation when blood oxygen levels decline. Three oxygen-sensing enzyme complexes may be used for this purpose: 1) mitochondrial electron transport chain metabolism, 2) heme oxygenase 2 (HO-2)-generating CO, and/or 3) an NAD(P)H oxidase (NOX). We hypothesize that intracellular redox changes are the link between the sensor and nervous signals. To test this hypothesis type I cell autofluorescence of flavoproteins (Fp) and NAD(P)H within the mouse CB ex vivo was recorded as Fp/(Fp+NAD(P)H) redox ratio. CB type I cell redox ratio transiently declined with the onset of hypoxia. Upon reoxygenation, CB type I cells showed a significantly increased redox ratio. As a control organ, the non-oxygen-sensing sympathetic superior cervical ganglion (SCG) showed a continuously reduced redox ratio upon hypoxia. CN−, diphenyleneiodonium, or reactive oxygen species influenced chemoreceptor discharge (CND) with subsequent loss of O2 sensitivity and inhibited hypoxic Fp reduction only in the CB but not in SCG Fp, indicating a specific role of Fp in the oxygen-sensing process. Hypoxia-induced changes in CB type I cell redox ratio affected peptidyl prolyl isomerase Pin1, which is believed to colocalize with the NADPH oxidase subunit p47phox in the cell membrane to trigger the opening of potassium channels. We postulate that hypoxia-induced changes in the Fp-mediated redox ratio of the CB regulate the Pin1/p47phox tandem to alter type I cell potassium channels and therewith CND.

Loss of Cervical Sympathetic Chain Input to the Superior Cervical Ganglia Affects the Ventilatory Responses to Hypoxic Challenge in Freely-Moving C57BL6 Mice

“…As such, it is proposed that HXC activates a carotid sinus (chemoafferent) nerve-brainstemdescending spinal cord pathway that increases pre-ganglionic sympathetic nerve activity, which in turn activates postganglionic neurons in the SCG, including those projecting to the carotid body via the GGN. It should be noted that there is compelling evidence that SCG cells are not directly responsive to hypoxia (Rigual et al, 1999;Nunes et al, 2012;Buckler and Turner, 2013;Gao et al, 2019;Bernardini et al, 2020), although there is equally compelling evidence that SCG cells [and in particular small intensely fluorescent (SIF) cells] are hypoxiasensitive (Hanson et al, 1986;Brokaw and Hansen, 1987;Dinger et al, 1993;Strosznajder, 1997;Nunes et al, 2010Nunes et al, , 2012.…”

Mitochondrial Succinate Metabolism and Reactive Oxygen Species Are Important but Not Essential for Eliciting Carotid Body and Ventilatory Responses to Hypoxia in the Rat

“…The pharmacological approach used makes it difficult to separate out potential redundant control mechanisms, with those that are acting in parallel. If redundant mechanisms were at play in the current investigation, then they must have been induced very rapidly as pharmacological interventions were only applied for a maximum of 1 h. The lack of complete elimination of the response to hypoxia in the presence of DMM, MitoT, and SKQ1 also does not rule out the involvement of other mediators independent of mitochondrial function including H 2 S [ 45 , 46 ] and ROS derived from other sources such as NADPH oxidase [ 47 , 48 ]. Whilst mitoROS may be elevated in hypoxia, in other compartments, they may be decreased and the specific interactions between ROS and ion channels require further investigation.…”

Hypoxia-dependent signaling in perioperative and critical care medicine

“…Additionally, local intermittent hypoxia occurs upon surgical manipulation of intestine and use of tourniquet [18,20]. Studies on hypoxic response mechanisms or hypoxic sensing have been preceded by electrophysiological studies, including the involvement of ion channels [24][25][26]. The presence of markers of the hypoxic state in tissues and cells is highly useful.…”