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American Journal of Respiratory and Critical Care Medicine Vol 166. pp. S17-S24, (2002)
© 2002 American Thoracic Society

Article

Airway Chemotransduction

From Oxygen Sensor to Cellular Effector

Paul J. Kemp, Anthony Lewis, Matthew E. Hartness, Gavin J. Searle, Paula Miller, Ita O'Kelly and Chris Peers

School of Biomedical Sciences and Institute for Cardiovascular Research, University of Leeds, Leeds, United Kingdom

Correspondence and requests for reprints should be addressed to Paul J. Kemp, School of Biomedical Sciences, Worsley Building, University of Leeds, Leeds, LS2 9JT UK. E-mail: p.z.kemp{at}leeds.ac.uk

ABSTRACT

The process of sensing, transducing, and acting on environmental cues is critical to normal physiologic function. Furthermore, dysfunction of this process can lead to the development of disease. This is especially true of the homeostatic mechanisms that have evolved to maintain the carriage of O2 to respiring tissues during acute hypoxic challenge. During periods of reduced O2 availability, three major mechanisms act conjointly to increase ventilation and optimize the ventilation–perfusion ratio throughout the lung by directing pulmonary blood flow to better ventilated areas of the lung. These mechanisms are as follows: (1) increased carotid sinus nerve discharge rate to the respiratory centers of the brain, (2) intrinsic hypoxic vasoconstriction of pulmonary resistance vessels, and (3) potential local and central modulation via stimulation of neuroepithelial bodies of the lung. The key to the rapid response to the O2 signal is the ability of each of these tissues to sense acutely the changes in PO2, to transduce the signal, and for cellular effectors to initiate compensatory mechanisms that will offset rapidly the reduction in PO2 before O2 availability to tissues is compromised. This review concentrates on the signal transduction mechanism that links altered PO2 to depolarization in the recently proposed airway chemosensory element, the neuroepithelial body (and its immortalized cellular counterpart, the H146 cell line), and discusses the pertinent similarities and differences that exist between airway, carotid body, and pulmonary arteriolar O2 sensing.

Key Words: hypoxia • potassium channels • tandem P domain

The ability to adapt to acute perturbation in environmental PO2 is crucial to survival. To optimize ventilation–perfusion matching, the pulmonary circulation must respond rapidly to hypoxia to deliver effectively sufficient O2 to metabolizing tissues in the face of compromised O2 availability. It does this by diverting blood to better ventilated parts of the lung and by increasing ventilatory drive to the respiratory musculature. Morphologic and functional studies have suggested strongly that neuroepithelial bodies (NEBs) of the lung could be key elements in this homeostatic process (for a recent review see Reference 1). There is compelling evidence to show that they respond to airway hypoxia as opposed to hypoxemia (2) and, therefore, would be predicted to act in concert with carotid body/aortic arch chemoreceptors (which sense oxygen levels in arterial blood [3]) and pulmonary smooth muscle cells (which possess intrinsic oxygen sensitivity [4]). The fundamental cellular basis of chemotransduction in two of the tissues (NEBs and carotid bodies) demonstrates surprising overlapping properties (although the molecular details differ) in that hypoxia leads to, sequentially, K+ channel inhibition, voltage-gated Ca2+ entry, and transmitter release. This scheme is, however, somewhat controversial in the pulmonary vasculature, with K+ channel involvement being variously implicated and dismissed (for a recent review see Reference 5).

POTENTIAL PHYSIOLOGIC ROLE OF NEBS

The prominence of NEBs in neonatal lungs (6) and the association of pathologic conditions such as apnea of prematurity and sudden infant death syndrome with NEB cell hyperplasia strongly suggest that these cells are involved in both the initiation of breathing at birth and cardiorespiratory control postnatally (7). This and other evidence detailed later suggest that they have the potential to act as airway O2-sensing elements where they may be intimately involved in optimization of ventilation-perfusion matching. NEBs are discrete clusters of cells located throughout the airways (1). They lie in contact with the airway lumen and are in close proximity to pulmonary vasculature (8, 9). They may evoke appropriate vascular responses by initiating afferent information to the respiratory centers (10) and by releasing peptides and amine modulators (particularly serotonin) into the local pulmonary circulation in hypoxia (8).

SIGNAL TRANSDUCTION BY NEBS AND THE ESTABLISHMENT OF A NEB CELL MODEL

Even some two decades after their proposition as O2 sensors, our knowledge of the cellular and molecular mechanisms underlying hypoxic transduction by NEB cells is still limited. This is due to the extreme difficulty in consistently isolating viable NEB cells for such studies. Electrophysiologic investigation of rodent NEB cells in culture and in intact slices of neonatal lung has facilitated the characterization of voltage-gated Na+, Ca2+, and K+ channels (11–13). Importantly, a component of the K+ current is reversibly inhibited by acute hypoxia (11). However, although these approaches have been used successfully to characterize both the nature of the sensor (employing lung slices from knockout mice [14]) and the pharmacologic profile of the O2-sensitive K+ channel, they are limited because they are inappropriate for acute molecular abrogation studies. Because the final aim of our studies is to define rigorously at the cellular and molecular levels, the transduction pathway(s) linking airway hypoxia to transmitter release, we reasoned that an immortalized cell line that mimics the known properties and responses of native NEB cells would first have to be established. To this end, we have, during the last 4 years, described such an alternative model: the small cell lung carcinoma line, H146 (15–21). These cells are derived from the same precursor pool as NEB cells (22), and they share numerous features, including the presence of serotonin, peptide transmitters, and voltage-gated ion channels (23). Using the whole-cell patch clamp technique, we have investigated the effects of acute hypoxia on voltage-gated ionic currents in H146 cells (18, 20) and compared these characteristics to those reported for native NEB cells (11, 12). NEB cells and H146 cells share remarkably similar electrophysiologic properties, including a large component of the K+ current that is depressed by acute hypoxia (Figure 1A) (18) and that controls resting membrane potential (Figure 1B) (20). Furthermore, graded hypoxia evokes graded K+ current inhibition (Figure 1C) (17), and these two O2-sensitive parameters are positively correlated (Figure 1D) (17). The upstream sensor in both cell types appears to be nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (14), a feature that distinguishes these cell types from other O2-sensing tissues (17).



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  		Figure 1. O2 sensitivity of K+ currents and membrane potential in H146 cells. (A) The top panels show exemplar whole-cell current traces before (C), during (H), and after (W) bath perfusion with hypoxic solution (PO2 at approximately 30 mm Hg) when employing either a stepping (top left) or ramp (protocol). Voltage protocols shown below the current traces. The lower panel shows a mean time course of hypoxic inhibition of normalized whole-cell K+ currents. The period of hypoxia is indicated by a horizontal bar. (B) The top panel shows an exemplar current clamp recording of resting membrane potential when hypoxia was applied alone or in the presence of 30-mM tetraethlyammoniun. Periods of hypoxia and tetraethylammonium are indicated by the horizontal bar. The bar graph in the lower panel is the mean membrane potentials measured in control or hypoxic solutions in the presence or absence of 30-mM TEA, as indicated at the top of each bar (TEA = tetraethlyammoniun); Con = control; Hy = hypoxia; Wash = washout. (C) Mean amplitudes of K+ current (open symbols) and membrane potential (solid symbols) during graded hypoxic challenges as shown on the x axis. (D) Correlation between membrane potential and K+ current magnitude at each grade of hypoxia.

 
THE NATURE OF THE SENSOR AND SIGNAL TRANSDUCTION

It has been widely agreed on for some time that candidate O2-sensing systems would, by definition, have the ability to respond rapidly and reversibly to altered environmental PO2 by undergoing oxidoreductase transitions. In chemosensory systems, there is direct evidence for the involvement of a variety of proteins, including plasma membrane-associated NADPH oxidase (13, 14, 17, 19, 24), mitochondrial electron chain complexes (25–27), and other heme-based proteins (28). In rodent NEBs and their human immortalized cellular counterparts (H146 cells), there is an accumulating body of evidence to suggest that the key event in airway O2 sensing is modulation of the cellular redox potential via substrate-limited turnover of NADPH oxidase (14, 17, 19, 24). The NADPH oxidase model for O2 chemoreception in airway suggests that under normoxic conditions the oxidase tonically generates superoxide from environmental O2, which is rapidly converted to hydrogen peroxide (H2O2) by a number of enzymes, including superoxide dismutase and catalase. This H2O2 is believed to promote channel activity and any reduction in H2O2 levels would, therefore, lead to K+ channel closure and cell depolarization. Thus, native, isolated, and cultured NEB cells express a number of important proteins that together constitute the multimeric functional NADPH oxidase enzyme complex, including gp91phox and p22phox24. Hypoxia causes decreased rhodamine 123 fluorescence (indicative of reduced free radical formation) and K+ channel inhibition, effects that are suppressed by the relatively nonselective NADPH oxidase inhibitor diphenylene iodonium (24). Furthermore, H2O2 was able to stimulate K+ channels (24). The suggestion that NADPH oxidase acts as O2 sensor and transduces the signal via changes in the intracellular redox potential was tested and extended in our human NEB model, H146 cells (18), by exploiting the fact that NADPH oxidase activity can be regulated by protein kinase C (PKC)-dependent phosphorylation of two components of the complex, p67phox and p47phox (29). During hypoxia, depression of H146 cellular H2O2 levels can be clearly demonstrated using the fluorescent dye, 2'7'-dichlorodihydrofluorescein diacetate (Figure 2A) (17). Central to this model is the idea that the primary effector (a K+ channel protein) must be able to respond H2O2. In H146 cells, the O2-sensitive K+ current is also 4-aminopyridine (AP)–insensitive (20), and activation of this 4-AP–insensitive K+ current by H2O2 is observed during hypoxic challenge (Figure 2B) (17). This response is not observed in normoxia (Figure 2B) (17) and is transient in nature (Figure 2B) (17). Together, these observations suggest that the K+ channels are maximally activated by the primary O2 sensing system in normoxia and that a sustained response may require altered activity of another sensory system. In evidence of an additional, converging sensory pathway being involved in hypoxic response of H146 is our recent observation that maximal inhibitory concentrations of two structurally unrelated inhibitors of NADPH oxidase activity, diphenylene iodonium and phenyl arsine oxide (PAO), are unable to abolish completely the hypoxic depression of K+ currents in this NEB cell model (19). Additional pathways notwithstanding, NADPH activity is central to the hypoxic response, and we have recently provided direct evidence that this response is dynamically downregulated by PKC activation. Treatment of H146 cells with the phorbol ester 12-O-tetradecanoylphorbol-13 acetate activates PKC, which increases the turnover of NADPH oxidase via translocation of the p47phox and p67phox subunits to the plasma membrane. Such activation results in augmented NADPH oxidase-dependent H2O2 production, which has little effect on K+ channel activity in normoxia as the channels are maximally active (see Figure 2B). However, in hypoxia, PKC activation results in a dramatic amelioration of the K+ current depression (Figure 2C) (17) simply because the cellular H2O2 levels cannot be reduced to a level normally associated with hypoxia in the absence of PKC activation. In other words, PKC activation results in maintenance of a relatively oxidized K+ channel environment even during hypoxic challenge, a process that is consistent with a PKC-dependent increase in O2 affinity as shown in Figure 2D (17). Recently, the involvement of NADPH oxidase has received further reinforcement from the observation that NEB cell K+ currents recorded from gp91phox knockout mouse lung slices are insensitive to acute hypoxia (14). Whether the quantitative contributions of this oxidase versus a further sensory pathway (which appear different in native NEB cells and the human model) are a result of species differences or cell type remains to be robustly investigated.



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  		Figure 2. Investigation in the mode and K+ channel inhibition by hypoxia in H146 cells. (A) Mean rate of change of fluorescence in cells loaded with 10-µM 2'7'-dichlorodihydrofluorescein diacetate during normoxic perfusion (top panel) or during hypoxic challenge. The insets show continuous time course flourescence of two exemplar cells. The periods of application of hypoxia are indicated by a horizontal bar. (B) The top panel show typical whole-cell K+ current recording during perfusion with 1-mM H2O2 in normoxic (top left) or hypoxia (top right). The lower panels show the mean time course of the K+ current amplitude measured at 0 mV. A period of application of H2O2 and hypoxia is indicated by the horizontal bars. (C) Typical whole-cell K+ currents (top panels) and mean time course of K+ current amplitude measured at 0 mV (center panel) during sequential application of 10-mM 4-amionpyridine and hypoxia in untreated cells (top left and center panels—open symbols) or cells treated with 10-nM 12-O-tetradecanoylphorbol-13 acetate (top right and center panel—solid symbols). Mean proportional 4 aminopyridine (AP)-sensitive currents in control (open bar) and after treatment with 12-O-tetradecanoylphorbol-13 acetate (hatched bar) are shown in the lower right, whereas the mean proportional O2-sensitive current in control (Con, open bar) and 12-O-tetradecanoylphorbol-13 acetate–treated (TPA, hatched bar) cells is shown in the lower right panel. (D) Kinetic plot (main panel) and transformed data (inset) show mean normalized current amplitudes at different PO2 values (TEA = tetraethlyammoniun). Closed circles = 100 nM TPA treatment TPA; open circles = untreated (control).

 
In the carotid body and pulmonary vasculature, the idea that NADPH oxidase provides the upstream signal for K+ channel inhibition lacks credence. For example, hypoxia-evoked catacholamine release from an in vitro preparation of intact carotid body is unaffected by the NADPH oxidase inhibitors, diphenylene iodonium, POA, and neopterin (30). Indeed, the heme protein dependence of the cellular response has been directly demonstrated in carotid body glomus cells in which hypoxic K+ channel inhibition is completely reversed upon application of carbon monoxide (28). The involvement of NADPH oxidase as an O2 sensor in the pulmonary circulation has similarly been directly discounted by the recent report that hypoxic pulmonary vasoconstriction is maintained in pulmonary arterioles isolated from gp91phox knockout mice (31).

It is clear, therefore, in the airway that the NEB cell primary O2 sensor is NADPH oxidase, whereas in the pulmonary vasculature and carotid body, it is not. However, one controversial mechanism that has been implicated in a variety of O2-sensitive tissues (32), including pulmonary arteriolar smooth muscle cells (26), is modulation of mitochondrial production of reactive oxygen species during hypoxia. In isolated perfused lung and pulmonary arteriolar smooth muscle cells, the hypoxic responses are dramatically reduced by selective inhibitors of electron transport complexes that act upstream of bc1 complex (rotenone, diphenylene iodonium, and myxothiazol), whereas downstream inhibitors (cyanide and antimycin A) are without effect. Confirmation of a major role for mitochondria was obtained from cells that lack mitochondria ({rho}o cells). In these cells, the hypoxic response was absent (26). These data have led to the hypothesis that during hypoxia, mitochondrial reactive oxygen species production is augmented, presumably because of altered O2 affinity of cytochrome oxidase, and this increase in reactive oxygen species levels affects the hypoxic response. Although the data are compelling in pulmonary vasculature, they are not entirely compatible with data from NEBs and H146 cells in which hypoxia causes decreased reactive oxygen species production (Figure 2A) (17, 24), decreased K+ channel activity (11–20, 33), and where H2O2 activates K+ currents (17, 24) (Figure 2B). We cannot completely discount mitochondrial involvement in carotid body chemosensing (although the precise mechanism may differ from the scheme presented previously here), as specific inhibitors of mitochondrial complexes mimic the actions of hypoxia in isolated carotid body glomus cells (27). However, recent evidence from our laboratory using {rho}o H146 cells have shown that mitochondrial depletion results in no diminution of acute hypoxic response: strong evidence in support of the lack of mitochondrial involvement in O2 sensing in these cells (15).

WHAT IS THE IDENTITY OF THE CHANNEL?

The amenability of H146 cells has allowed us to build rapidly on our initial findings and define the physiologic importance of this O2 sensitive K+ current. Thus, even in the presence of a maximally effective concentration of 4-AP, hypoxia causes membrane depolarization in H146 cells, demonstrating that H146 cells possess O2-sensitive K+ channels, similar to those in NEB cells, which influence cell membrane potential (see Figure 1A). The pharmacologic profile of this channel, coupled with its ability to govern membrane potential, suggests that it belongs to the tandem P-domain K+ channel (K2P) family (34). To address this in more detail, the H146 model has allowed rapid screening for the presence of messenger RNA encoding eight separate members of this family (16), an approach that would be technically very difficult in native NEB cells. Employing the primer pairs (Figure 3A) (16) directed against the published sequences of human K2P channels (TWIK1 and 2; TASK1, 2, and 3; TREK1 and 2; and TRAAK), only hTWIK1 and hTRAAK were not amplified from DNase-treated, reverse transcribed H146 cell messenger RNA (Figure 3A, top panel). Further pharmacologic profiling of the O2-sensitive K+ current–relative resistance to tetraethylammonium (Figures 1B [18] and 3B [16]), arachidonate and halothane sensitivity, and dithiothreitol resistance (16), together with our observations of Zn2+ (Figure 3C) and 4-AP resistance (20), suggested that TASK3 underlay the O2-sensitive current. Using a molecular abrogation approach, we found that an antisense probe directed against TASK3 and TASK1 (TASK1 involvement was already dismissed because of the Zn2+ resistance of the O2-sensitive current) was able to abolish almost completely the hypoxic K+ channel inhibition in these cells; misense and lipofectamine-only treated cells retained their ability to respond to hypoxia (Figure 4D) (16). Thus, the O2-sensitive channel in this immortalized model of NEB cells is the K2P channel, TASK3 (16). Whether this channel is expressed in native NEB cells is still under investigation. However, we have preliminary evidence to suggest, based on anandamide blockade of currents (anandamide is a selective blocker of recombinant TASK1 [35]), that TASK1 may be coupled to the O2 sensor in neonatal mouse NEB cells recorded in situ (Miller, Peers, and Kemp, unpublished observations). These data notwithstanding, it is clear that there are certain subtle differences in the properties of native and model airway-sensing cells. For example, the voltage-sensitive K+ channel Kv3.3a has been demonstrated to underlie a component of the rodent NEB cell O2-sensitive K+ current (24); whether this Kv channel is either expressed or responds to decreased O2 levels in H146 cells is currently under investigation.



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  		Figure 3. Pharmacologic and molecular biologic determination of the identity of the H146 cells O2-sensitive K+ channel. (A) Agarose gel (top panel) after reverse transcription-polymerase chain reaction screening for eight members of the K2P channel family, as indicated, using the panel of paired primers shown in the middle panel (expected product size and optimized annealing temperatures are shown in the fourth and fifth columns, respectively). Positive controls (genomic DNA amplification) are also shown for TWIK1 and TRAAK. Sequence alignment of the antisense and misense probe with each channel member is shown in the lower panel. (B) Exemplar whole-cell K+ currents (top panel) and time course (center panel) evoked by the ramp protocol (indicated in A) during hypoxia alone or during hypoxia in the presence of 1-mM TEA. Periods of application are indicated by the horizontal bars. The lower panel shows the correlation between the control hypoxic response and the response to hypoxia in the presence of TEA. (C) Exemplar whole cell K+ currents (top panel) and time course (center panel) evoked by the ramp protocol indicated during hypoxia alone or during hypoxia in the presence of 100-µM ZnCl2. Periods of application are indicated by the horizontal bars. The lower panel shows the correlation between the control hypoxic response and the response to hypoxia in the presence of ZnCl2. (D) Mean time courses of hypoxic inhibition of K+ currents measured at 0 mV after treatment of cells for 5 days with missense (top panel) or antisense oligodeoxynucleotides directed against hTASK3. Periods of application are indicated by the horizontal bars. The lower panel shows the mean hypoxic inhibition either in control (lipafectamine only) or after antisense or missense treatment, as indicated (TEA = tetraethylammonium).

 


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  		Figure 4. Characterization of hypoxic-sensitivity of recombinant hTASK1. (A) Immunocytochemical localization of hTASK in HEK293 cells transfected with empty vector (left panels) or vector containing the full open reading frame of hTASK1 (right panels). The lower panel shows an exemplar time course of hTASK currents during alteration of external pH as indicted. (B) Typical ramp-evoked K+ currents recorded from hTASK1-transfected cells at the pH values indicated are shown in the top panel, and the mean titration curve is shown in the lower panel. (C) In the upper panel is the mean time course of hypoxic inhibition of hTASK K+ currents. A period of application of hypoxia is shown by the horizontal bar. The lower panel shows exemplar hTASK1 ramp currents during hypoxic inhibition at pH 8.4 and 5.4 (as indicated). (D) The upper panel shows a typical time course of the effect of hypoxia under alkaline and acidic conditions. Periods of hypoxic perfusion are indicated by the horizontal bars, and pH values are shown above the time series. The lower panel plots the positive correlation between pH and O2 sensitivity.

 
There is also evidence for the involvement of K2P channels in O2 signal transduction in other chemosensory tissues (36, 37). Thus, TASK1 has been implicated indirectly in carotid body glomus cell O2 sensitivity (37) and suggested to be involved in maintenance of resting membrane potential in isolated pulmonary artery smooth muscle cells (36). These are exciting electrophysiologic observations in native tissues. They now have a molecular and functional correlate evidenced by our recent recombinant studies demonstrating directly that human TASK1, when expressed HEK293 cells (Figure 4A) (38), demonstrates both the expected pH sensitivity (Figures 4A and 4B) (38) and, most importantly, is reversibly and rapidly inhibited (Figure 4C) (38), in a pH-sensitive manner (Figures 4C and 4D) (38), as O2 availability is reduced.

CONCLUSION
A potential locus of airway O2 sensing is at the NEB. Evidence is emerging from both native NEBs and the NEB cell model, the H146 cell line, that the primary O2 sensor is the membrane-associated NADPH oxidase. In hypoxia, this enzyme initiates hypoxic inhibition of a K+ channel (which may be one or both of TASK3 or Kv3.3a) via a substrate-dependent reduction in the cellular redox potential that will lead to downstream cellular effects such as voltage-gated Ca2+ entry and transmitter release (Figure 5) . The H146 cell line is not alone among O2-sensing tissues in expressing this specific K+ channel type, and it is tempting to speculate that hypoxic suppression of TASK-like K+ channels may represent a unifying theme in O2 chemotransduction.



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  		Figure 5. The proposed transduction pathway for NEBs and their immortalized human cellular counterparts, H146 cells. H146 cells and native NEBs share a common primary O2 sensor, NADPH oxidase. Hypoxia results in substrate-delimited production of reactive oxygen species and H2O2. Reduction in the cellular redox potential results in closure of TASK3 K+ channels in H146 cells and K+ channels, which may include Kv3.3a in native rodent NEBs. In both cell types, the resultant depolarization would lead Ca2+-dependent release of vasoactive amines.

 
FOOTNOTES

Supported by The British Heart Foundation and The Wellcome Trust.

Received in original form June 14, 2002; accepted in final form October 7, 2002

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