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¹ School of Biosciences, Museum Avenue, Cardiff University, Cardiff CF11 9BX, UK

Abstract

The majority of physiological processes proceed most favourably when O₂ is in plentiful supply. However, there are a number of physiological and pathological circumstances in which this supply is reduced either acutely or chronically. A crucial homeostatic response to such arterial hypoxaemia is carotid body excitation and a resultant increase in ventilation. Central to this response in carotid body, and many other chemosensory tissues, is the rapid inhibition of ion channels by hypoxia. Since the first direct demonstration of hypoxia-evoked depression in K⁺ channel activity, the numbers of mechanisms which have been proposed to serve as the primary O₂ sensor have been almost as numerous as the experimental strategies with which to probe their nature. Three of the current favourite candidate mechanisms are mitochondria, AMP-activated kinase and haemoxygenase-2; a fourth proposal has been NADPH oxidase, but recent evidence suggests that this enzyme plays a secondary role in the O₂-sensing process. All of these proposals have attractive points, but none can fully reconcile all of the data which have accumulated over the last two decades or so, suggesting that there may, in fact, not be a unique sensing system even within a single cell type. This latter point is key, because it implies that the ability of a cell to respond appropriately to decreased O₂ availability is biologically so important that several mechanisms have evolved to ensure that cellular function is never compromised during moderate to severe hypoxic insult.

(Received 26 May 2006; accepted after revision 10 July 2006; first published online 20 July 2006)
Corresponding author P. J. Kemp: School of Biosciences, Museum Avenue, Cardiff University, Cardiff CF11 9BX, UK. Email: kemp{at}cf.ac.uk

Terrestrial mammalian life has evolved to perform optimally at an atmospheric partial pressure of oxygen (P_O2) at, or around, 150 mmHg. Gaseous exchange and mixing at the alveoli of the lungs results in a mild O₂ gradient from inspired to alveolar air and, as a result, there is a reduction in systemic P_O2 to around 100 mmHg. However, there are a number of physiological and pathological circumstances in which this P_O2 is reduced either acutely or chronically. For example, renal medullary P_O2 is below 50 mmHg (Johannes et al. 2006) and mean cerebral blood P_O2 is closer to 20 mmHg (Hoffman et al. 1999). Thus, nephron function and central neuronal activity are both chronically adapted to these relatively hypoxic environments. Pathologically, several cardiorespiratory diseases result in chronic or intermittent reduction in systemic and/or pulmonary P_O2. These include sleep apnoea, congestive heart failure, emphysema and chronic obstructive pulmonary disease, all of which affect a significant proportion of the adult population. Such hypoxic insult may either be directly causal to certain life-threatening conditions, such as pulmonary hypertension, or increase susceptibility to others, such as stroke.

A crucial physiological response to arterial hypoxaemia is an increase in afferent traffic from the carotid body to the respiratory centres in the brainstem. Such input results in increased rate and depth of ventilation. Airway hypoxia elicits a vasoconstrictor response in the pulmonary resistance arterioles. Although such vasoconstriction appears to be ably accounted for by direct action on the smooth muscle, one can speculate that the response may be modulated by input from the neuroepithelial bodies of the lung. Interestingly, neuroepithelial bodies release serotonin in response to acute hypoxia both in vivo (Lauweryns et al. 1978) and in vitro (Fu et al. 2002), and this release may control pulmonary vascular tone (Yelmen et al. 2003) and possibly provide ascending input (Lauweryns & Van, 1982) via a number of afferent pathways (Adriaensen et al. 2003).

Central to the cardiorespiratory responses of almost all the chemosensory tissue is the rapid inhibition of ion channels by hypoxia, a notion first demonstrated in 1988 in glomus cells isolated from rabbit carotid body (Lopez-Barneo et al. 1988). This hypoxia-evoked K⁺ channel inhibition was apparently membrane delimited and required no diffusible factors, leading these authors to suggest either that the K⁺ channel itself was innately oxygen sensitive or that the O₂ sensor was an integral component of the K⁺ channel protein complex. Thus, the ‘membrane hypothesis’ of chemotransduction by the mammalian carotid body was born. In the 18 years that have elapsed since these seminal observations, the search for the acute O₂ sensor within each specialized O₂-sensing cell type has become akin to a holy grail for researchers in the field. Indeed, there have been almost as many candidate O₂ sensors as there are experimental strategies with which to probe their nature. Moreover, the membrane hypothesis itself has been challenged by at least two independent observations showing the requirement for cytosolic factors in hypoxic K⁺ channel inhibition (Wyatt & Peers, 1995; Buckler, 1997). However, over the last decade or so, it has become clear that there is unlikely to be a unifying mechanism to account for O₂ sensing in all tissues, and it is probable that there may not even be a single sensing system within each cell type. This latter point is key because it implies that the ability of a cell to respond appropriately to decreased O₂ availability is so important that several mechanisms have been put in place to ensure that cellular integrity is not compromised during hypoxic insult.

Inhibition of K⁺ channels by hypoxia has been documented in many native cell types (for review see Lopez-Barneo et al. 2001). Thus, acute hypoxic modulation of K⁺ channel activity is central to chemosensing in carotid body (Lopez-Barneo et al. 1988; Peers, 1990; Buckler, 1997), neuroepithelial body (Youngson et al. 1993; Fu et al. 1999) and its immortalized cellular counterpart (H146 cells; O'Kelly et al. 1998, 1999, 2000; Hartness et al. 2001) and, perhaps controversially, the pulmonary circulation (Yuan et al. 1995; Ward & Aaronson, 1999; Hulme et al. 1999). In addition, such O₂ sensitivity is believed to play a significant role in modulation of excitability in several cellular components of the mammalian nervous system (Jiang & Haddad, 1994; Vergara et al. 1998; Coppock et al. 2001; Plant et al. 2002) and immune system (Conforti et al. 2003; Szigligeti et al. 2006).

There is widespread agreement that the glomus cells of the carotid body release a variety of transmitter substances, including acetylcholine (Eyzaguirre & Zapata, 1968), dopamine (Fidone et al. 1982; Rigual et al. 1986; Vicario et al. 2000) and ATP (Zhang et al. 2000), in response to decreased systemic P_O2 and initiate an increase in afferent discharge. Similarly, there is a general consensus regarding the fact that decreased P_O2 leads to membrane depolarization (Wyatt et al. 1995), activation of voltage-gated Ca²⁺ channels (Benot & Lopez-Barneo, 1990) and Ca²⁺-dependent transmitter release (Urena et al. 1994; Pardal et al. 2000). However, the details of the upstream sensing machinery are still terribly contentious. Indeed, even the identity of the K⁺ channel effector in carotid body glomus cells is hotly debated. Thus, although there is certainly species specificity, investigators working in near-identical cellular models report conflicting evidence. In the rat, there is clear difference of opinion, with either a voltage-activated, Ca²⁺-sensitive, large-conductance (BK_Ca) or an open-rectifying, acid-sensitive member of the tandem P domain K⁺ channel family (TASK) being implicated in the fundamental process of O₂ sensing. Evidence for BK_Ca channels comes from whole-cell (Peers, 1990; Wyatt & Peers, 1995) and excised patch-clamp data (Riesco-Fagundo et al. 2001) from isolated glomus cells and complementary amperometric data from intact carotid body slices (Pardal et al. 2000). Suggestions of a background, leak K⁺ channel-dependent O₂ sensitivity have been substantiated by patch-clamp data in isolated rat glomus cells (Buckler, 1997) and supported by in situ hybridization employing a probe to the K⁺ channel, TASK1 (Buckler et al. 2000). Since it is clear that both channel types are expressed in rat carotid body, and that they are both inhibited by hypoxia in recombinant systems (Lewis et al. 2001, 2002), it seems reasonable to assume that they may act in concert to produce the appropriate physiological response, an idea which has not been investigated robustly to date. In rabbit carotid body, one of the O₂-sensitive K⁺ channels is an inactivating, 4-aminopyridine-sensitive conductance (Lopez-Barneo et al. 1993). This conductance has not been fully characterized at the molecular level but is clearly of the voltage-activated (Kv) family of K⁺ channel genes. Indeed, dominant negative strategies have shown a lack of involvement of Kv1 (Perez-Garcia et al. 2000), and comparative electrophysiology and molecular screening have implicated Kv4.1/Kv4.3 as hypoxia-sensitive K⁺ channels in this species (Sanchez et al. 2002). Oxygen-sensitive human Ether-A-Go-Go (hERG) K⁺ channels are also expressed in the rabbit carotid body (Overholt et al. 2000), suggesting that, as in the rat, multiple K⁺ channels may also be involved in the full-blown hypoxic response in this species. In mouse thus far, the situation appears less complex, and the Kv3 family appears to be the most likely O₂-sensitve K⁺ channel candidate (Perez-Garcia et al. 2004).

Further difference of opinion surrounds the potential identity of the O₂ sensor itself. Over the last 20 years, proposed mechanisms have included: (a) NADPH oxidase; (b) mitochondria (Wyatt & Buckler, 2004); (c) AMP kinase (Evans et al. 2005); and (d) haemoxygenase-2 (Williams et al. 2004a).

In the presence of molecular O₂, NADPH oxidase produces reactive O₂ species and H₂O₂, and was first described in activated neutrophils (Babior et al. 1975; Curnutte et al. 1975). The production of superoxide and its subsequent dismutation to H₂O₂ endows the enzyme system with a second messenger system which might regulate, either directly or indirectly, the activity of key ion channels in the carotid body. Although the response to changes in redox state is not clear for TASK-like channel activity, redox regulation of BK_Ca channels is well documented (Tang et al. 2001, 2004; Zeng et al. 2003; McCartney et al. 2005). However, a role for this multicomponent oxidase as the primary O₂ sensor in carotid body was disconfirmed following the observation that gp91 knock-out mice (which have no functional NADPH oxidase activity) demonstrate unaltered carotid body responses to hypoxia (Roy et al. 2000). Parallel studies also demonstrated the lack of involvement of NADPH oxidase in pulmonary smooth muscle contraction (Archer et al. 1999) even though it is an essential component of the O₂-sensing system in airway chemoreceptors (O'Kelly et al. 2000; Fu et al. 2000). Recently, a study in the p47^phox knock-out mouse (which has reduced enzyme activity) has demonstrated that NADPH oxidase may, after all, be involved in carotid body O₂ sensing, but it is now suggested that enzyme-dependent activation of K⁺ channels might provide an inhibitory influence on the glomus cell excitability (He et al. 2005).

Another source of reactive O₂ species is the mitochondria. Although still somewhat controversial, the idea that there is a paradoxical increase in generation of reactive O₂ species by mitochondria during hypoxia is slowly gaining momentum (Chandel & Schumacker, 2000). Current understanding of how hypoxia induces an increase in reactive O₂ species is by no means complete, but electron transfer at the Rieske iron–sulphur centre of mitochondrial complex III is certainly involved (Brunelle et al. 2005). Although such a model of O₂ sensing has been demonstrated in cultured pulmonary smooth muscle cells (Waypa et al. 2001) and intact arterioles (Leach et al. 2001), mitochondria do not appear to play a significant role in O₂ sensing in the neuroepithelial cellular model (Searle et al. 2002) and their contribution to carotid body function during hypoxia is still contentious. Indeed, only recently did two contemporaneous reports demonstrate that electron transport makes either a significant contribution (Wyatt & Buckler, 2004) or no contribution whatsoever (Piruat et al. 2004) to O₂ sensing by glomus cells. Recent controversies notwithstanding, mitochondrial signalling is still an attractive proposal since it provides a link between O₂ sensing and metabolism.

AMP-activated protein kinase (for review see Hardie & Sakamoto, 2006) has recently been proposed as an O₂-sensing mechanism in carotid body and pulmonary arterioles (Evans et al. 2005), again connecting cellular function during hypoxia to metabolic status. In this model, hypoxia evokes an increase in AMP/ATP ratio of sufficient magnitude to augment AMP-activated protein kinase activity via phosphorylation. In turn, AMP kinase activation elicits an increase in intracellular Ca²⁺ concentration which results in pulmonary arteriolar constriction or carotid body excitation (Evans et al. 2005); any direct interaction between AMP kinase and K⁺ channels has yet to be published.

Both native (Riesco-Fagundo et al. 2001) and recombinant BK_Ca channels (Lewis et al. 2002) are inhibited by hypoxia in excised, inside-out membrane patches. In order to define this membrane-delimited molecular mechanism which might link decreased P_O2 to K⁺ channel inhibition, we have employed functional proteomics to identify BK_Ca -subunit protein partners and have then determined the role(s) of such partners in K⁺ channel O₂ sensing. Two O₂-dependent enzymes were identified by BK immunoprecipitation followed by mass spectrometry of trypsin digests (trypsin mass mapping). These were -glutamyl transpeptidase and haemoxygenase-2 (Williams et al. 2004a,b). Pharmacological and genetic manipulations of -glutamyl transpeptidase were ineffective at modulating hypoxic inhibition of BK_Ca (Williams et al. 2004b). However, BK_Ca channel activity was robustly and reversibly activated by the downstream products of haemoxygenase-2, biliverdin and CO. In the presence of O₂, addition of the haemoxygenase-2 cosubstrates, haem and NADPH, evoked an increase in channel activity which was dramatically reversed by hypoxia. RNA interference (blocking haemoxygenase-2 translation) depressed tonic channel activity, and the NADPH/haem-dependent hypoxic channel suppression was completely absent. Carbon monoxide rescued this loss of function. Importantly, BK_Ca channels from isolated rat glomus cells behaved in a parallel fashion. Although we have only demonstrated a role for haemoxygenase-2 in the O₂ sensitivity of a particular K⁺ channel, our observations are consistent with earlier data of others from the carotid body and are suggestive of a role for this enzyme in the physiological responses to acute hypoxia. Thus, the carotid body expresses haemoxygenase-2 protein and is capable of synthesizing CO (Prabhakar et al. 1995). Furthermore, similar to our experiments employing recombinant BK_Ca, CO is capable of activating native BK_Ca in glomus cells of the carotid body (Riesco-Fagundo et al. 2001). Interestingly, data from sinus nerve recordings show that blockers of haemoxygenase-2 increase carotid body activity, which is consistent with the idea that haemoxygenase-2 provides a tonic depression in activity via CO-evoked hyperpolarization. According to this model, acute hypoxia would reduce CO production and release this inhibitory influence (Prabhakar, 1999). However, haemoxygenase-2 knock-out mice demonstrate a severely blunted hypoxic ventilatory response (Adachi et al. 2004), suggesting that chronic reduction in CO levels impairs peripheral O₂ sensing. Such impairment might result from inactivation of voltage-gated Na⁺ or Ca²⁺ channels in glomus cells that are chronically depolarized in the absence of adequate CO. Whatever the mechanism at the tissue and whole-animal level, it seems likely, therefore, that the BK_Ca/haemoxygenase-2 system represents another acute O₂ sensor.

Almost two decades after the first direct evidence that hypoxia evoked K⁺ channel inhibition in the carotid body, we still have no sensing mechanism which can reconcile the majority of whole-animal, tissue and cellular data. Each proposal has its attractive elements but none, in isolation, can fully explain how the carotid body detects and reacts to acute systemic hypoxaemia. As suggested towards the beginning of this article, the ability to respond appropriately to hypoxia might be so fundamental that cells cannot leave their fate in the hands of a single mechanism. If this is indeed the case, the challenge is less about who remains standing when the music stops, and more about understanding the complex interactions which may be occurring between each of the candidates.

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Acknowledgements

This work was funded by the British Heart Foundation.

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