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Rocher, A.; Aaronson, P.I. K+ Channels in O2 Sensing. Encyclopedia. Available online: https://encyclopedia.pub/entry/55469 (accessed on 14 April 2024).
Rocher A, Aaronson PI. K+ Channels in O2 Sensing. Encyclopedia. Available at: https://encyclopedia.pub/entry/55469. Accessed April 14, 2024.
Rocher, Asuncion, Philip I. Aaronson. "K+ Channels in O2 Sensing" Encyclopedia, https://encyclopedia.pub/entry/55469 (accessed April 14, 2024).
Rocher, A., & Aaronson, P.I. (2024, February 26). K+ Channels in O2 Sensing. In Encyclopedia. https://encyclopedia.pub/entry/55469
Rocher, Asuncion and Philip I. Aaronson. "K+ Channels in O2 Sensing." Encyclopedia. Web. 26 February, 2024.
K+ Channels in O2 Sensing
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O2 sensing is a fundamental biological process necessary for the acute and chronic responses to varying environmental O2 levels which allow organisms to adapt to hypoxia. Whereas chronic responses depend on the modulation of hypoxia-inducible transcription factors which determine the expression of numerous genes encoding enzymes, transporters and growth factors, acute responses rely mainly on the dynamic modulation of ion channels by hypoxia, causing adaptive changes in cell excitability, contractility and secretory activity in specialized tissues.

O2 sensing carotid body hypoxia hypoxic pulmonary vasoconstriction

1. Physiological Oxygen Sensing: The Carotid Body as an O2 Sensor

Complex aerobic organisms, such as mammals, must maintain adequate circulating O2 levels (PaO2) to ensure a sufficient supply of oxygen for their metabolic needs. To fulfill this homeostatic function, organisms possess strategically located specialized structures to monitor PaO2 and activate compensatory mechanisms which enable its stabilization. These mechanisms act mainly on the respiratory and circulatory apparatus to mediate enhanced ventilation and pulmonary O2 exchange, improved blood transport at the systemic level and optimal distribution at the tissue level. The structures responsible for these responses include: (i) the chemoreceptor cells of the carotid body (and to a lesser degree the aortic bodies), which in situations of hypoxia reflexively increase pulmonary ventilation and cardiac activity [1][2]; (ii) the vascular smooth muscle cells of the pulmonary arteries (PASMC), in which a vasoconstriction to hypoxia (hypoxic pulmonary vasoconstriction or HPV) in poorly ventilated areas produces a redistribution of pulmonary blood flow essential to match perfusion to ventilation, thus ensuring an improvement in pulmonary blood oxygenation and, therefore, PaO2 [3]; (iii) the neuroepithelial bodies of the pulmonary airways, which reflexively and together with the above contribute to optimal ventilation–perfusion adjustments [4]; and (iv) neonatal adrenal medullary chromaffin cells, which play a key role in the respiratory adaptation of the newborn to hypoxia associated with delivery and extrauterine life [5].
All these systems share a high sensitivity to hypoxia with a low threshold and high gain (i.e., they respond to moderate hypoxia), with a level of metabolic activity that progressively increases with the intensity of hypoxia. Each, through changes in excitability, contractility or secretory activity, promotes acute physiological responses, such as HPV and the hypoxic ventilatory response (HVR), which occur within seconds or minutes and enhance the supply of O2 to tissues.
Hyperventilation as a response to high-altitude hypoxia was appreciated by early high-altitude physiologist-expeditioners, although it was Gay-Lussac who first recorded the symptoms he suffered during his balloon flights to verify various aspects of the gas laws (1804). In 1868, the German physiologist Pflüger described the hyperventilation produced by breathing pure nitrogen [6], and in 1908, Boycott and Haldane described in detail the ventilatory effects of hypoxia of different intensities as hyperventilation with increased frequency and depth of respiratory movements, although it was not then known how the decrease in PaO2 could produce these effects [7].
In 1928, Fernando de Castro, a disciple of Cajal, discovered that the carotid body (CB), until then considered a sympathetic ganglion (ganglium minutum) or a gland (glandula carotica), was a sensory organ innervated by a sensory nerve: the carotid sinus nerve (CSN) or Hering’s nerve. De Castro also noticed the close relationship between the epithelioid cells of the CB (today called type I, glomus or chemoreceptor cells) and the blood capillaries on one hand and sensory nerve endings on the other. He proposed that the organ is specialized to detect changes in the chemical composition of the blood and that the epithelioid cells are the sensors [8]. In 1930, Corneille Heymans discovered that the hyperventilation caused by hypoxia was a reflex originating in the carotid sinus region. This discovery led to his being awarded the Nobel Prize in Physiology and Medicine in 1938, even though until at least 1936 he confused the carotid sinus with the carotid body [9].
CB chemoreceptors have an adaptive function since they detect the PaO2 and, upon its decrease, initiate reflexes aimed at increasing the pumping of air rich in O2 from the atmosphere to the alveoli. However, the mechanisms of CB function at the cellular level have been an enigma for many years. A multitude of hypotheses have arisen, including the “Metabolic hypothesis” of the Russian School of Physiology and the “Acid hypothesis” of Winder and the Oxford School, which emerged initially.
Of these, the one that achieved the widest dissemination was the metabolic hypothesis [10], which linked the chemoreception mechanism to the process of cellular respiration. Hypoxia, like metabolic poisons which act on the mitochondria and are strong stimulants of the CB, would act by reducing ATP levels in chemoreceptor cells. The fall in ATP would trigger neurotransmitter release by chemoreceptor cells, although the theory did not explain how this would occur. In support of this hypothesis, there is extensive evidence that the mitochondria in CBCC are specifically adapted for O2 sensing. Whereas in most tissues PO2 must be reduced to very low levels before O2 availability significantly limits respiration, the oxygen sensitivity of mitochondrial function in chemoreceptor cells, an intrinsic property of the Complex 4, appears to be abnormally high. Thus, even at relatively high PO2, electron flux through the respiratory chain would be diminished, thereby decreasing respiration and ATP synthesis in the CBCC. In these cells, mitochondrial depolarization and accumulation of NADH may occur with a relatively modest decline in PO2 to below 40–20 Torr, levels undetected in most other cell types, as first shown by Mills and Jobsis [11][12], who by spectrophotometric analysis correlated changes in NADH/NAD+ ratio with afferent nerve activity over a wide range of O2 levels describing the presence of both a high-affinity and a low-affinity cytochrome a3. These results were confirmed by Duchen and Biscoe [13][14], who found that the NADH/NAD ratio changed at a PO2 of nearly 60 mmHg and increased as hypoxic challenges became more severe [15]. In rat CBCC, Buckler and Turner obtained P50 values for the effects of oxygen on NADH, electron transport and cytochrome oxidase activity of 40, 5.4 and 2.6 mmHg, respectively [16]. These values are at least one order of magnitude greater than those reported in other tissues and are compatible with a role for mitochondrial metabolism in oxygen sensing. Furthermore, recent evidence suggests that chemoreceptor cells have a different mitochondrial gene expression signature that confers the intrinsically diminished oxygen sensitivity compared to that of other cells. Three atypical mitochondrial electron transport chain subunits, Ndufa4l2, Cox4i2 and Cox8b, are among the most specifically expressed genes in CBCC, highlighting their potential roles in mitochondria-mediated oxygen sensing [17][18]. Along these lines, conditional deletion of Cox4i2 in tyrosine-hydroxylase-positive cells (TH+) diminishes both the chemoreceptor cell and ventilatory response to hypoxia in the mouse [19].
In the late 1980s, several observations, including those from Constancio González’s group, led to the proposal known as the “Membrane model” as an alternative hypothesis. By means of biochemical and pharmacological studies, Almaraz et al. [20] demonstrated that depolarization of CB using high extracellular K+ induced Ca2+-dependent release of dopamine. Rocher et al. [21] found that veratridine, a voltage-dependent Na+ channel activator, induced dopamine release in a tetrodotoxin (TTX)-sensitive and Ca2+-dependent manner, and that hypoxia-induced release is inhibited by dihydropyridines, revealing for the first time the excitability of the chemoreceptor cells.
At the same time, in a collaboration between the laboratories of Prof. González in Valladolid and Prof. López-Barneo in Sevilla, the excitable nature of rabbit CBCC in primary culture was confirmed, and the first PO2-regulated ion channel was discovered: low PO2 produced a reversible inhibition of a transient K+ current of type IA [1][22]. The existence of hypoxia-sensitive K+ currents in the CB was quickly extended to all animal species studied including cat, rat and mouse. In the rat, the hypoxia-sensitive K+ current was ascribed to the high-conductance Ca2+-dependent K+ channel (BKCa) [23] and a K+ ‘leak’ current was shown to be due to TASK-1 channels [24][25]. These findings led to the “Membrane hypothesis” of chemotransduction [2], which proposes that the transduction process relies on K+ channels that are reversibly inhibited by hypoxia, thus triggering depolarization, activation of Na+ [26] and Ca2+ channels [27][28] and a resulting increase in intracellular Ca2+, which triggers the release of neurotransmitters to activate afferent chemosensory fibers of the CSN [29][30][31].

2. Oxygen-Sensitive K+ Channels in the Carotid Body

Since the first report of the reversible inhibition by hypoxia of K+ channels in rabbit CBCC [1], identifying the hypoxia-sensitive K+ channels has been of paramount interest for the understanding of hypoxic transduction. K+ channels constitute the largest and most diverse family of ion channels. They are ubiquitously expressed in both excitable and non-excitable cells in all organisms, and their open probabilities can be regulated by voltage, Ca2+ and various neurotransmitters and second messengers. Studies of cloned K+ channels have revealed that they are hydrophobic protein complexes which generally consist of tetramers of transmembrane pore-forming α-subunits, each of which is bound to an accessory β-subunit which regulates channel kinetics and membrane trafficking [32][33].
Based on the topology and structure of the α-subunits, researchers can speak of three groups of O2-sensitive K+ channels (KO2) found in the CB. The first group, voltage-gated K+ channels (KV), are tetramers of 4 α-subunits, each having 6 α-helical transmembrane-spanning (TMS) units and a P-loop (6TM/1P), with the latter contributing to the formation of the channel pore in the assembled tetramer. The second group, to which the BKCa channel belongs, is a tetramer of subunits with 7 transmembrane segments and a P-loop (7TM/1P). A third group, which includes leak channels, possesses 4 transmembrane segments and two pore-forming domains (4TM/2P). Unlike the other groups that form tetramers, these channels are formed of dimers, which are not known to associate with specific β-subunits [34].

2.1. KV Channels and Oxygen Sensitivity in the Carotid Body

Twelve families (KV1.x–KV12.x) of KV channels have been identified in mammalian cells, each consisting of several different subfamilies with multiple isoforms (e.g., KV1.1–1.9, KV2.1–2.2, …, etc.; see [35]). KV5-6 and KV8-9 family subunits are electrically silent; they cannot assemble into channels by themselves but can form functional hetero-multimers with KV2.x subunits, thereby altering the kinetics of the KV2.x channel current [36]. Channel opening occurs when membrane depolarization causes a change in the configuration of the α-subunits due to the outward movement within the membrane of the S4 TMS units, which contain several positively charged arginine residues. KV α-subunits are associated with auxiliary subunits that protrude into the cytoplasm and modulate their activity; the first ones described, termed KVβ subunits [37][38], associate with KV1.x and KV4.x channels.
When talking about KV channels in hypoxic transduction, researchers cannot forget the regulatory β-subunits as they may be necessary for their coupling to the putative O2 sensor and could play a very important role in regulating the response [39][40]. The kinetic properties of the channel when only the α-subunit is expressed in a model system can be quite different from those observed in the cell in its natural state, which, however, are seen when the α- and the β-subunits are co-expressed [32][33]. KV channel structure and regulation by β-subunits are the subject of an excellent recent review by Abbott [41].
As mentioned above, the first hypoxia-sensitive K+ channel, a KV channel that is reversibly inhibited by decreasing PO2, was described in rabbit CBCC. It is a voltage-dependent inactivating current with kinetic properties typical of a delayed rectifier, with a macroscopic activation threshold close to −40 mV [1]. Detailed kinetic and pharmacological characterizations of KV currents in rabbit CB have been reported [42][43].
It can be a significant challenge to match native KV currents in intact cells with the KVα- and β-subunits forming the channels that mediate them. However, several K+ channel genes expressed in chemoreceptor cells have been identified, and some of them have been shown to behave as KO2 in heterologous expression systems. In rabbit CB, using dominant-negative constructs to block the expression of KV1 (shaker) and KV4 (shal) family channels, Perez-Garcia et al. [44] found that only adenoviral infections with KV4.xDN suppressed the transient KV current in CBCC and prevented hypoxia-induced depolarization, suggesting that native KO2 currents are carried mainly by channels of the KV4 subfamily. Immunological blockade of K+ channels with anti-KV4.3 further supported this conclusion [45]. In a detailed molecular study [46], the subunits identified in rabbit CBCC were KV3.4, KV4.1 and KV4.3, whereas in mouse CB, the subunits described belonged to the KV2 and KV3 families, specifically KV2.2, KV3.1, KV3.2 and KV3.3 [47]. However, it seems that in both species, not all the isoforms found represent the molecular correlate of the KO2 currents but may have other physiological functions [48]. Other KV α subunits that are reversibly inhibited by hypoxia when expressed in PASMCs or in heterologous systems are KV1.2, KV1.5, KV2.1, KV3.1b, KV4.2 and KV2.1/9.3 [49][50]. Of these, channels incorporating KV1.5 seem to be of predominant importance in O2 sensing in PASMCs.
The role of the KV channels as triggers of CB activity has been questioned. If the membrane potential (Em) is close to −55mV [28] and the KV activation threshold is close to −40 mV, this implies that the channel is not active at rest (in normoxia) and that its inhibition by hypoxia cannot initiate depolarization. However, it can be argued that: (i) at an Em of −55 mV, the probability of opening may be too low to be readily apparent, but nonetheless sufficient to depolarize the cells when further decreased due to the high membrane input resistance, or (ii) the cells possess spontaneous electrogenesis [51], making it possible for the K+ channel to be recruited and inhibited. Accordingly, there are data indicating that an O2-sensitive KV current in rabbit CBCC participates in setting the membrane potential and that, therefore, its inhibition could depolarize the cell [22][52]. In contrast, Wang and Kim [53] showed that KV in isolated rat CBCC were mostly closed at rest but became active when cells were depolarized in response to hypoxia and that this strongly limited the hypoxia-induced rise in [Ca2+]i. These findings suggest that KV channels, rather than mediating hypoxic activation of CBCC, provide a hyperpolarizing force, which limits the magnitude of the hypoxic response.

2.2. BKCa Channels and Oxygen Sensitivity in the Carotid Body

In the rat CBCC, the first PO2-sensitive current to be described was found to be due to the high-conductance BKCa channel [23], which is activated by both depolarization and a rise in [Ca2+]i. These have been described in a wide variety of tissues and cells, both excitable and non-excitable, including nerve cells, muscle cells, pituitary cells, chromaffin cells, and renal tubules among, others [54][55].
BKca channels consist of α-subunit tetramers with seven transmembrane domains (S0–S6) [56][57]. Segment S4 acts as a voltage sensor, and a region between segments S5 and S6 forms the selectivity filter and the channel pore [58]. In addition to the body or core formed by the transmembrane segments, BKCa channels have a very long carboxyl-terminal tail, which constitutes two-thirds of the protein and contains four hydrophobic segments (S7–S10) and several alternative splicing sites. There is a region between segments S9 and S10 with numerous negatively charged residues, mostly aspartate, which is highly conserved between species. This region is known as the “calcium bowl” and appears to be responsible for Ca2+ binding and channel activation by Ca2+ [59][60]. Regulatory β-subunits are also essential for BKCa activity since their co-expression with the channel α-subunit significantly alters the functional properties of the channel [56]. There are four types of β-subunits (β1–β4) with differential expression depending on the tissue [32]; the channel has been found to be much more sensitive to voltage and Ca2+ when α- and β-subunit types are transfected together than when only the one is transfected [61]. The structure and regulation of BKCa channels have recently been reviewed by Guntur et al. [62].
As shown by Peers’ group, BKCa channels in the rat CBCC are active at the resting Em, and their specific inhibition by hypoxia leads to membrane depolarization. The role of BKCa in the transduction of the hypoxic stimulus is supported on the basis that the BKCa blocker charybdotoxin (CHTX) depolarizes type I cells [63][64]. It has also been shown that the blockers iberiotoxin (IBTX) and tetraethylammonium (TEA), like hypoxia, evoke dopamine release in rat or mouse CB slice preparations [65]. The O2-modulation of BKCa in rat CBCC at the single channel level was characterized by Riesco-Fagundo et al. [66]. Its activity seems to be very much dependent on the recording configuration used; channel activity is low in inside-out patches (free of cytosolic factors) and high in vesicles studied using the perforated patch technique, which retain a small volume of cytosol [63].
However, the possibility that BKCa channels are involved in depolarization of CBCC seems counterintuitive, since in numerous cell types they are involved in processes in which Ca2+ signaling is coupled to hyperpolarization, rather than depolarization. In fact, BKCa channels play a particularly important role in neuronal signaling by facilitating repolarization after the action potential, thus contributing to the regulation of neurotransmitter release at the synaptic terminal [54]. In other cases, such as during smooth muscle contraction or exocytosis in secretory cells, the hyperpolarization induced by the activation of these channels is a negative feedback mechanism that contributes to terminate these processes by determining the closure of voltage-dependent Ca2+ channels [67].
In addition, many authors question whether a voltage- and calcium-dependent channel could be the trigger of CB activity. Its high conductance does not seem well suited to providing a background K+ flux for setting the membrane potential, and its reactivation by [Ca2+]i during hypoxic stimulation would tend to oppose depolarization. Furthermore, a large body of publications and experimental data from several laboratories argue against such a role. For example, Buckler [24][25] demonstrated that neither TEA nor CHTX modifies membrane potential, intracellular Ca2+ or the response to hypoxia. Lahiri et al. [68] and Donnelly et al. [69] similarly found that BKCa does not participate in either the intracellular Ca2+ increase produced by hypoxia or in the secretory response of CBCC. Gonzalez’s group also reported that neither TEA nor IBTX alters basal catecholamine release, intracellular Ca2+ or the hypoxia-induced secretory response [70]. These studies concluded that BKCa was not relevant for hypoxia transduction and/or that it possessed other undisclosed functions.
The contradictory findings and different proposed roles for BKCa and KV led Wang and Kim [53] to re-examine the role of these voltage-dependent K+ channels in basal excitability and in the generation of the hypoxic response in rat CBCC. They showed that TEA/4-AP had no effect on basal [Ca2+]i, suggesting that BKCa and KV were insufficiently active at rest to participate in initiating the hypoxic response. However, TEA/4-AP caused an increase in [Ca2+]i in chemoreceptor cells previously depolarized by high extracellular K+, indicating that BKCa and KV were basally open in these cells. These channels became active when cells depolarized in response to hypoxia and strongly limited the rise in [Ca2+]i. Furthermore, hypoxia had no effect on BKCa in cell-attached patches of fully depolarized cells with a resting Em of 0 mV, showing that activation of BKCa observed under hypoxia was due to cell depolarization. The authors proposed that the role of KV and BKCa channels is to limit the hypoxia response by opposing membrane depolarization and the opening of voltage-gated Ca2+ channels [53]. Since these findings contradicted previous observations in the literature [66][71], the authors argued that the BKCa current present in CBCC of various rat strains (i.e., Wistar vs. Sprague-Dale) might be modulated differently by hypoxia, possibly due to the expression of different BKCa isoforms or splice variants [53].
Notwithstanding these observations, as argued by Peers and Wyatt [72] and Lopez-Barneo [73] in support of a role for BKCa channels in O2 sensing in CBCC, there is a danger that the contribution of BKCa or KV channels to the physiological behavior of chemoreceptor cells may be underestimated by studies carried out using isolated cells or excised patches, since in the intact CB, these cells are closely packed with their neighbors within the glomus and may be electrically coupled [74] or subjected to autocrine and paracrine interactions, which could exert depolarizing influences and modify the cell resting potential or [Ca2+]i such that a fraction of KV or BKCa channels are open. Also, regardless of whether hypoxic inhibition of BKCa channels initiates depolarization in chemoreceptor cells, there can be no doubt that their inhibition would delay repolarization and thereby amplify and sustain the hypoxic response.
Diverse endogenous molecules, including heme, carbon monoxide (CO) and reactive oxygen/nitrogen species (ROS/RNS), have been reported to activate BKCa channels [75][76]. The association between BKCa and the heme provides an explanation for the direct modulation of the channel by both hypoxia and gaseous second messengers including CO and NO. Although these gases can use intracellular signaling pathways, they can also modulate BKCa channels in isolated membrane patches [66][77]. A study by Jaggar et al. [78] proposed the interesting hypothesis that CO can stimulate BKCa channels by altering its binding to the heme. In the absence of CO, the heme binds to BKCa, inhibiting its activity, whereas in the presence of CO, the interaction between the channel and the heme is weakened, and the tonic inhibition produced by the latter disappears, resulting in current activation.
The involvement of the interaction between CO, heme and BKCa in O2 sensing was proposed by Kemp’s group [79], who used two-dimensional electrophoresis and mass spectrometry studies to show that heme oxygenase-2 (HO-2), which is expressed in CBCC [80], co-precipitates with the BKCa α-subunit expressed in heterologous systems. The authors proposed that the association of BKCa with the heme group and HO-2 facilitates the production of CO in close proximity to the channel which favors channel modulation [79].
In the presence of O2 and using NADPH as a cofactor, HO catalyzes the degradation of the heme producing biliverdin, iron and CO. In hypoxia, CO production is slower than under normoxia because the breakdown of hemoglobin by HO which it depends upon requires O2. Given that CO (as well as O2) activates K+ channels, it was proposed that the response to hypoxia would be partly the result of a decrease in this CO-mediated activation [79]. This effect of hypoxia was verified in HEK-293 cells stably expressing BKCa channels. However, this does not explain the observation that hypoxia inhibits BKCa in isolated inside-out patches, because HO-2 needs the substrate (heme) and both O2 and NADPH as co-substrates to inhibit the channel, and none of these would be present in excised inside-out patches. Furthermore, hypoxia was able to cause a modest inhibition of BKCa channel activity even when HO-2 was inactive, suggesting the involvement of an additional mechanism. Additionally, Lopez-Barneo’s group demonstrated that O2 sensing by the mouse CB is largely unaffected by HO-2 knockouts [81]. This suggests that a major role for BKCa channels in CB chemotransduction may be restricted to the rat.
Interesting also was the observation made by McCartney et al. [82], who, in a heterologous system, described a highly conserved sequence within a cysteine-rich domain at the carboxy-terminal end of BKCa, that they termed STREX (stress-regulated exon), directly inhibited by hypoxia in excised membrane patches. They suggested that this motif is what confers the channel’s sensitivity to hypoxia and that variability in its expression due to alternative splicing is what gives rise to the plasticity of cellular responses to hypoxia in different tissues. The mechanism by which STREX renders the channel sensitive to hypoxia was not defined but was dependent upon the presence of a Cys–Ser–Cys motif and did not involve CO. The proposition was attractive, since STREX was the sensor, and therefore a membrane-limited mechanism in addition to HO-2 could contribute to hypoxic inhibition of these channels. However, Ross et al. [83] found that rat CBCC, a species in which BKCa is sensitive to hypoxia, does not express this variant of the channel.
Mark Evans and colleagues presented evidence for an additional mechanism for oxygen sensing and BKCa channels in rat chemoreceptor cells, involving AMP-activated protein kinase (AMPK) [84][85][86]. AMPK is activated by a rise in the cytosolic AMP/ATP ratio, acting as a tuned metabolic sensor. Given the low concentration of AMP under normal conditions relative to ATP concentration (very low AMP/ATP), a slight predominance of ATP degradation over ATP regeneration could markedly increase the AMP concentration and activate the enzyme. AMPK can phosphorylate a multitude of proteins, including the BKCa channel, which is inhibited by phosphorylation. However, subsequent work by Evans and co-workers [87][88] showed that whereas global knockout of AMPK α1 + α2 abolished the ventilatory response to hypoxia, the CB itself was still fully sensitive to hypoxia. This indicated that AMPK plays a crucial role in the response to hypoxia at sites downstream of the CB, probably in the brainstem, rather than in CBCC. Interestingly, they also presented evidence that knocking out Liver Kinase B1 (LKB1), which phosphorylates AMPK, severely depresses the hypoxic response in CBCC, but via an AMPK-independent mechanism, and speculated that LKB1 may act on the mitochondria in these cells to maintain ATP synthesis, a lack of which could impede O2 sensing through several mechanisms [88].
The activity of BKCa channels is regulated, not only by O2 and CO but also by hydrogen sulfide (H2S), which acts as an inhibitor of these channels, suggesting that integration of these signals may be crucial to the physiological response of the CB. The intracellular concentration of H2S depends on the balance between its enzymatic generation and its mitochondrial breakdown. Kenneth Olson, the originator of the concept that H2S is involved in O2 sensing, showed that hypoxia increased sulfide production by cell homogenates and suggests that a rise in cellular [sulfide] may act as an O2-sensing mechanism that occurs ubiquitously because hypoxia depresses the breakdown of H2S, without interfering with its ongoing synthesis [89][90]. Conversely, it has been proposed that hypoxia increases cellular sulfide production in CBCC through a mechanism involving CO [91]. According to this model, during normoxia, the enzyme HO-2 generates CO, but hypoxia inhibits its production. The decrease in CO leads to a decrease in protein kinase G-dependent phosphorylation of the enzyme cystathionine γ-lyase (CSE), which causes an increased production of H2S. Prabhakar’s group knocked out the enzyme responsible for generating H2S in mice, cystathionine-γ-lyase (CSE), and observed that this interfered with oxygen sensing in the CB [92] and, based on evidence that application of H2S blocks BKCa currents in CBCC [93][94], they proposed that an increased sulfide synthesis by CSE could account for hypoxia-induced inhibition of the BKCa current and CBCC activation.
This mechanism is brought into question by studies that have indicated that the pharmacological block of CSE and cystathionine-β-synthase (CBS), another important sulfide-generating enzyme, did not prevent the hypoxia-induced inhibition of the TASK current or the rise in [Ca2+]i in CBCC [95] and that knockout of HO-2 [81] and CSE [96] has no effect on acute oxygen sensing in the CB.
Importantly, however, H2S, which is thought to be present at very low concentrations within cells, exists in equilibrium with substantial amounts of other intracellular sulfur-containing species, including polysulfides and persulfides [97], which are mainly synthesized by sulfurtransferases such as cysteinyl tRNA synthetases (CARS) [98]. In a process analogous to that mediated by ROS, these reactive sulfur species (RSS) can alter protein function via cysteine sulfuration. This has led to the suggestion [99] that RSS rather than H2S may mediate O2 sensing. Moreover, sulfurtransferases can also directly sulfurate proteins and could therefore also have a signaling function [98]. Whereas it has been argued [100] that H2S is unlikely to be an O2 sensor in CBCC since its high membrane permeability would prevent it from reaching a cellular concentration sufficient to inhibit mitochondrial function, this would not be an issue if hypoxia was acting by increasing (RSS) or promoting direct enzyme-mediated sulfuration. Likewise, evidence that O2 sensing persists in CSE knockouts does not rule out a role for RSS, since they are generated by multiple enzymatic and non-enzymatic pathways [97]. Nevertheless, although it is not known whether RSS affect K+ channels in CBCC, both H2S and the polysulfide Na2S4 have been reported to greatly slow the inactivation of KV3.4 channels expressed in HEK 293T cells [101]. This suggests that H2S/RSS would be likely to depress rather than increase responsiveness to hypoxia if KV channels expressed in CBCC are similarly regulated.

2.3. K2P Channels and Oxygen Sensitivity in the Carotid Body

In 1997, Buckler presented evidence that TASK channels, which belong to the K2P channel family, play an important role in O2 sensing in CBCC [24][25]. K2P is another K+ channel family in which the α-subunits are made up of four transmembrane domains. They have two pores instead of the single pore formed by the other K+ channel families (hence the designation K2Pore) and exist as dimers in the membrane. They are voltage-and ligand-independent channels that are constitutively open, allowing them to generate leak or background currents. Eight different types of K2P have been cloned in rodents and humans and can be grouped according to their sensitivity to different stimuli, including TWIK-1 and TWIK-2 (Tandem of P domains in Weak Inward rectifier K+ channels), TREK-1, TREK-2 (TWIK Related K+ channels), TRAAK (TWIK Related Arachidonic Acid stimulated K+ channels, which are activated by polyunsaturated fatty acids and by distension), KCNK6 and KCNK7 (silent subunits), and finally the TASKs: TWIK related Acid-Sensitive K+ channels [102]. In addition to the two best known, TASK-1 and TASK-2, functional TASK-3 and TASK-4 channels and a fifth non-functional type, TASK-5, have been described in different tissues [103][104][105][106][107]; each K2P channel has its own expression pattern and each tissue its own combination of channels [102][108]. The structure, function and regulation of TASK and other K2P channels are described in a recent review by Sepulveda et al. [109].
Pharmacologically, TASK-1, TASK-2 and TASK-3 are insensitive to TEA and 4-AP, and although many drugs modify TASK activity, there is no specific activator or inhibitor of any of these channels. This complicates their functional analysis, although information about their roles in regulating the membrane potential can be gleaned by using the variety of semi-selective drugs available. For example, TASK-2 is inhibited by quinine, quinidine and clofilium. Zn2+ is a better inhibitor of TASK-1, which also appears to be blocked by quinidine, Ba2+ and low concentrations of the endocannabinoid anandamide [110]. TASK-1, TASK-2 and TASK-3 are inhibited by the local anesthetic lidocaine and bupivacaine [111] and are opened by volatile anesthetics such as halothane and isoflurane [112].
As previously mentioned, the voltage dependence of KV and BKCa currents creates a certain degree of uncertainty regarding their functionality: if the activation threshold of hypoxia-sensitive channels is close to −40mV and the resting membrane potential (Em) varies between −50 and −60mV, in normoxia these channels would be closed and, therefore, hypoxia would not be able to reduce their Po. In rat CBCC, Buckler’s experiments revealed the existence of a low-conductance O2-sensitive K+ leak current, which has very little voltage dependence, is reversibly inhibited by hypoxia and was responsible for the initial depolarization of the CBCC [24]. Although Buckler identified the channel that carries this current as TASK-1 by its biophysical properties [25][113], other channels of the same family, such as TASK-3 or TASK-1/TASK-3 dimers, seem to contribute to the current. Patch-clamp recordings with activators and inhibitors of TASK-type channels showed that, pharmacologically, the O2-sensitive background current of CBCC more closely resembles TASK-3, whereas the conductance and biophysical properties are closer to those of TASK-1 [114][115]. There is evidence that TASK-1 and TASK-3 channels can form heterodimers and can associate with other proteins that could alter their characteristics [116][117]. TASK-1/TASK-3 currents are sensitive to pH, which would also explain the CB response to acidosis. TASK-1/TASK-3 is also sensitive to metabolic poisons that activate CB such as cyanide and DNP [25][113] but resistant to the classical K+-channel inhibitors TEA and 4-AP [24]. In addition to TASK-1 and TASK-3, TASK-2, TASK-5, TREK-2 and TRAAK have been found in CB sections using immunohistochemical techniques [118].
Although gene deletion of TASK-3 in mice was reported to have no effect on the ventilatory response to hypoxia (HVR), deletion of the TASK-1 gene reduced the HVR and depressed the chemoafferent (CSN) response to hypoxia in vitro [119]. Double knockout of both TASK-1 and TASK-3 similarly reduced the ventilatory and chemoreceptor nerve responses to hypoxia but did not completely abolish them [119]. However, in studies performed on CB slices, constitutive deletion of TASK-3 and/or TASK-1 appeared to have little effect on Ca2+ signaling or neurosecretion in response to hypoxia [120]. One explanation for this apparent discrepancy is that the chronic loss of TASK1 and/or TASK3 is largely compensated for in some way. Interestingly, enzymatically dispersed Task1/Task3-null chemoreceptor cells have a relatively depolarized resting potential relative to controls, which could promote a compensatory involvement of KV or other ion channels in the hypoxic response [73][120]. However, the nature of any compensatory response that could maintain O2 sensing following TASK channel knockout in the glomus cells has not yet been defined.
It is important to note that the hypoxia sensitivity of these leak channels, which is evident in cell-attached recordings, is absent in inside-out excised patches, implying that their O2 sensitivity depends on some soluble cytoplasmic factor [66][113]. One cellular constituent that probably plays a key role in maintaining TASK channel activity is MgATP, because the addition of millimolar levels of ATP to the intracellular side of excised patches results in a rapid increase of channel activity [114][121]. Thus, although they are often referred to as oxygen-sensitive ion channels, there is no evidence that TASK channels are directly sensitive to oxygen.
Buckler proposed that TASK-type channels are constitutively open, and close with hypoxia and acidosis, and that these channels, and not KV or BKCa, are responsible for the CB depolarization and neurosecretion [115][122]. Buckler’s proposal provides a compelling explanation for how hypoxia activates CBCC, but other aspects such as the intrinsic sensitivity of the cell membrane to hypoxia remain to be resolved.
Finally, it is important to appreciate that the depolarization of any cell reflects a shift in the balance between Na+ influx and K+ efflux. In glomus cells, hypoxic inhibition of K+ efflux tilts the balance in favor of Na+ influx. It is widely thought that Na+ influx is via a voltage-independent background channel. A calcium-activated non-selective cation channel with a conductance of 20-pS has been described in isolated rat glomus cells and exhibits properties like those of Ca2+-activated monovalent cation channels such as TRPM4 and TRPM5 [123]. It is activated only during moderate-to-severe hypoxia (<5% O2) due to the necessary intracellular calcium elevation (via voltage-gated Ca2+ channels) and thus would contribute to positive feedback driving further membrane depolarization and Ca2+ influx. Thus, O2 sensing would involve both inhibition of an outward K+ current and activation of an inward Na+ current.

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