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INVITED REVIEW

HIGHLIGHTED TOPICS
Oxygen Sensing in Health and Disease

Regulation of oxygen sensing by ion channels

Laboratorio de Investigaciones Biomédicas, Departamento de Fisiología and Hospital Universitario Virgen del Rocío, Universidad de Sevilla, E-41013 Seville, Spain

	ABSTRACT

TOP ABSTRACT ACUTE RESPONSES TO HYPOXIA... MECHANISMS OF O2 SENSING... EFFECTS OF CHRONIC HYPOXIA... PATHOPHYSIOLOGY ASSOCIATED WITH... FUTURE RESEARCH DIRECTIONS ACKNOWLEDGMENTS REFERENCES

 
O₂ sensing is of critical importance for cell survival and adaptation of living organisms to changing environments or physiological conditions. O₂-sensitive ion channels are major effectors of the cellular responses to hypoxia. These channels are preferentially found in excitable neurosecretory cells (glomus cells of the carotid body, cells in the neuroepithelial bodies of the lung, and neonatal adrenal chromaffin cells), which mediate fast cardiorespiratory adjustments to hypoxia. O₂-sensitive channels are also expressed in the pulmonary and systemic arterial smooth muscle cells where they participate in the vasomotor responses to low O₂ tension (particularly in hypoxic pulmonary vasoconstriction). The mechanisms underlying O₂ sensing and how the O₂ sensors interact with the ion channels remain unknown. Recent advances in the field give different support to the various current hypotheses. Besides the participation of ion channels in acute O₂ sensing, they also contribute to the gene program developed under chronic hypoxia. Gene expression of T-type calcium channels is upregulated by hypoxia through the same hypoxiainducible factor-dependent signaling pathway utilized by the classical O₂-regulated genes. Alteration of acute or chronic O₂ sensing by ion channels could participate in the pathophysiology of human diseases, such as sudden infant death syndrome or primary pulmonary hypertension.

Electrophysiology; Gene Expression; Hypoxia-Inducible Factors

View larger version (19K): [in this window] [in a new window]   Fig. 1. Hypoxia signaling pathway with indication of the major adaptive responses to acute and chronic hypoxia.

In this review, we summarize the participation of ion channels in the cellular and systemic adaptive responses to hypoxia. We discuss the role of ion channels as effectors of the hypoxia signal transduction pathway in cells acutely responding to low PO₂, emphasizing the present hypotheses on the mechanisms underlying O₂ detection. We also stress the growing importance of ion channels as part of the gene expression program triggered by chronic hypoxia. Finally, we comment on the pathophysiological implications of acute and chronic regulation of ion channel function by O₂ tension.

	ACUTE RESPONSES TO HYPOXIA MEDIATED BY ION CHANNELS

TOP ABSTRACT ACUTE RESPONSES TO HYPOXIA... MECHANISMS OF O2 SENSING... EFFECTS OF CHRONIC HYPOXIA... PATHOPHYSIOLOGY ASSOCIATED WITH... FUTURE RESEARCH DIRECTIONS ACKNOWLEDGMENTS REFERENCES

 
Changes of local O₂ tension can induce modifications in the electrical activity of numerous cell types, including neurons; however, neurosecretory cells located in chemoreceptor organs and smooth muscle cells in pulmonary and systemic arteries are those directly involved in the major systemic adjustments to acute hypoxia.

O₂-Sensitive Neurosecretory Cells

The carotid and aortic bodies or the neuroepithelial bodies of the lung, which are organs capable of sensing global O₂ tension, participate in the compensatory cardiorespiratory adjustments to hypoxia. These organs contain O₂-sensitive neurosecretory cells, which release transmitters on exposure to environmental low PO₂ (<50 to 60 Torr) (40). The classical O₂-sensing chemoreceptors are the carotid bodies, composed of clusters of sensory (glomus) cells innervated by afferent nerve fibers. These sensory fibers convey chemosensory discharges to the brain stem respiratory center to evoke hyperventilation during hypoxemia. Similar clusters of excitable neurosecretory cells have also been described in the neuroepithelial bodies of the lung and in adrenal chromaffin cells from the neonate where they detect PO₂ changes in the inspired air and in blood, respectively. Excitation of chemoreceptor cells by hypoxia mainly depends on the presence of membrane channels whose activity is modulated by low PO₂. The "O₂-sensitive" channels studied in more detail are K⁺ channels, initially described in glomus cells of the carotid body (7, 15, 23, 39, 53, 71) and found in all the hypoxia-responsive neurosecretory cells studied so far (61, 75, 87, 92). Nevertheless, the kind of O₂-sensitive K⁺ channel appears to change among the various chemoreceptor cells or among cells in different animal species. Some K⁺-channel types proposed to participate in acute O₂ sensing are voltage-dependent channels of the voltage-gated K⁺ (Kv) or Shaker family, Ca²⁺-activated K⁺ (K_Ca) channels, and TASK-like background K⁺ channels (see Refs. 38 and 40 and references therein). Recordings illustrating the reversible inhibition by hypoxia of whole cell K⁺ currents in several chemoreceptor cell types are shown in Fig. 2A, and the "membrane model" of chemosensory transduction is summarized by a scheme in Fig. 2B. At least in the case of carotid body glomus cells, all of the indicated steps involved in stimulus-secretion coupling have strong experimental support. Transmitter release induced by hypoxia in isolated cells is 1) mimicked by depolarization with high extracellular K⁺ or application of K⁺ channels blockers (51, 78), 2) paralleled by an increase in cytosolic Ca²⁺ concentration ([Ca²⁺]) (44, 78), and 3) abolished by removal of extracellular Ca²⁺ or blockade of voltage-gated Ca²⁺ channels (44, 78). In addition, it has directly been shown in patch-clamped cells that hypoxia or K⁺-channel blockers produce glomus cell depolarization (8, 85) and an increase of action potential firing frequency (8, 41, 44). The rise of cytosolic [Ca²⁺] induced by hypoxia is prevented in voltage-clamped cells held at negative membrane potentials (8). Altogether, these data indicate that chemosensory transduction is initiated by the closure of K⁺ channels by low PO₂, which leads to membrane depolarization and/or increase of action potential firing frequency, extracellular Ca²⁺ influx through voltage-gated channels, and transmitter release to the extracellular milieu (38).

View larger version (23K): [in this window] [in a new window]   Fig. 2. A: reversible reduction of macroscopic K+ currents by hypoxia in 4 representative O2-sensitive neurosecretory cells. B: scheme of the membrane model of O2 sensing in neurosecretory cells. [Ca2+], Ca2+ concentration; CNS, central nervous system; IK, K+ current.

Vascular Smooth Muscle Cells

Vascular smooth muscle cells (VSMCs) control blood flow and tone, and their contraction is directly influenced by blood O₂ tension. The acute vascular responses to hypoxia studied in more detail are pulmonary vasoconstriction and dilation of systemic vessels (82, 91).

Hypoxia-induced vasoconstriction (pulmonary vasculature). Hypoxic pulmonary vasoconstriction (HPV), which occurs predominantly in small resistance arteries, is essential for fetal life because it helps to maintain the high pulmonary vascular resistance that diverts blood through the ductus arteriosus. In adults, HPV reduces blood flow through poorly ventilated alveoli, thus contributing to matching perfusion to ventilation and preventing systemic hypoxemia when atelectasis is present. Although the adaptive changes of pulmonary myocytes to low PO₂ are complex, these cells respond, similar to the O₂-sensitive neurosecretory cells, with reduction in amplitude of the macroscopic voltage-dependent K⁺ currents (49, 56, 89, 90). Inhibition of one or several types of K⁺ channels by hypoxia leads to membrane depolarization, opening of voltage-gated Ca²⁺ channels, and myocyte contraction (82, 89).

Hypoxia-induced vasodilation. Hypoxic vasodilation is another fast response to hypoxia of VSMCs, particularly well manifested in coronary and cerebral vessels, that helps to increase the perfusion of blood to the O₂-deprived tissues. A major component of hypoxic vasodilation is mediated by ATP-sensitive K⁺ (K_ATP) channels of vascular myocytes, which open in response to hypoxia due to decreased ATP production (13). However, there are other O₂-sensitive ionic mechanisms causing myocyte relaxation because it occurs with PO₂ levels that do not compromise energy metabolism. K_Ca channels potentiated by low PO₂ have been described in isolated cerebral resistance myocytes (24), and a somewhat similar mechanism (inhibition of K⁺ channels by normoxia) has been proposed to induce contraction of the ductus arteriosus at birth once the blood in the newborn is oxygenated (77). Moreover, there is considerable evidence indicating that, in arterial myocytes, transmembrane Ca²⁺ influx is also directly inhibited by low PO₂. Relaxation by hypoxia is produced in arteries precontracted with K⁺ (a condition that prevents repolarization by opening of K_ATP or K_Ca channels), and in isolated myocytes the elevation of cytosolic [Ca²⁺] induced by high K⁺ concentration is reversibly reduced by low PO₂ (20, 79). Inhibition of L-type Ca²⁺ channels by hypoxia has been described in patch-clamped systemic arterial myocytes (20, 21, 68).

	MECHANISMS OF O2 SENSING BY ION CHANNELS

TOP ABSTRACT ACUTE RESPONSES TO HYPOXIA... MECHANISMS OF O2 SENSING... EFFECTS OF CHRONIC HYPOXIA... PATHOPHYSIOLOGY ASSOCIATED WITH... FUTURE RESEARCH DIRECTIONS ACKNOWLEDGMENTS REFERENCES

 
O₂ Sensor in Close Contact with the Ion Channels

Although the role of ion channels as effectors in the acute cellular responses to hypoxia is well established, the identity of the O₂ sensor molecules and the signaling pathways linking the sensors to the effectors remain, however, enigmatic. Because some channels retain the hypoxia responsiveness in excised membrane patches, it has been suggested that the O₂ sensor is closely associated with the channel oligomer, either attached to the pore-forming -subunit or as part of an auxiliary subunit (23, 32, 37, 59). Switching of the sensor between oxi- and deoxi-conformations would result in alteration of the channel gating owing to direct allosteric interactions. Some specific types of K⁺ channel - and/or -subunits are expressed in O₂-sensitive cells (4, 10, 14, 25, 30, 62). The levels of protein expression of Kv1.5 and Kv3.1 as well as Kv1.1 subunits are reported to be higher in pulmonary resistance arterial myocytes than in other arterial VSMCs (10). It has been shown that mice lacking the Kv1.5 subunits have impaired HPV and reduced sensitivity of whole cell voltage-gated K⁺ currents to hypoxia (2) and that antibodies against Kv2.1 diminish O₂-sensitive currents in rat pulmonary myocytes (30). However, whether Kv1.5, Kv2.1, or any other K⁺ channel -subunit acts as an O₂ sensor or whether they are simply effectors in the hypoxia signaling cascade of pulmonary VSMCs is not known. Some recombinant subunits of K⁺ and Ca²⁺ channels expressed in heterologous cells have been shown to be O₂ sensitive (18, 31, 35, 36, 50, 52). These studies lead us to expect rapid progress in the identification of the O₂ sensors; however, advances produced so far have been relatively minor, and the data available are inconclusive. The O₂ sensitivity of or combinations of and K⁺ and Ca²⁺ channel subunits changes, depending on the experimental conditions used in the various laboratories and on the cell types used for heterologous protein expression (see Ref. 40 for a detailed discussion). Therefore, it seems that O₂ sensitivity is not absolutely intrinsic to the ion channels but requires the interaction between the O₂-sensing signaling molecules and the pore-forming channel subunits.

Redox Model of Acute O₂ Sensing

An alternative view to the existence of an O₂ sensor attached to the ion channels is the redox model of O₂ sensing based on the conversion of O₂ into reactive oxygen species (ROS), which would then alter the cellular redox status and the function of the ion channels (which contain numerous residues susceptible to redox modification) (1, 11). The two ROS-producing systems postulated as O₂ sensors are the NADPH oxidase and mitochondria.

NADPH oxidase as possible O₂ sensor. NADPH oxidase has been proposed to transduce O₂ levels by changing the rate of superoxide anion () production, which after conversion to H₂O₂ oxidizes ion channels (11). Although mice lacking the gp91 catalytic subunit of the neutrophil's oxidase have impaired O₂ sensitivity of airway chemoreceptor cells (22), the hypoxia responsiveness of carotid bodies (60), neonatal adrenal medulla (74), and pulmonary VSMCs (3) remains unaltered. Furthermore, the histological appearance of glomus cells and the modulation of the O₂-sensitive K⁺ current by PO₂ are also unchanged in the gp91 mutant mice (27). Surprisingly, this same group reported that genetic suppression of another component of the neutrophil's oxidase (p47^phox) results in mutant mice with increased basal activity in the carotid sinus nerve and exacerbated ventilatory response to hypoxia (63). Whether this phenotype, reflecting overexcitability of the glomus cell-afferent fiber synapse, is a nonspecific side effect of the p47^phox deletion or whether it is due to selective alteration of the carotid body O₂-sensing machinery is presently unknown. Although these studies may suggest that the phagocytic NADPH oxidase is not a general O₂ sensor, other isoforms, existing in numerous tissues (see Ref. 38), could participate in O₂ sensing.

Mitochondria as possible O₂ sensor. Mitochondria have also been considered by some authors to be the site for acute O₂ sensing because, similar to hypoxia, inhibitors of the electron transport chain (ETC) and metabolic poisons stimulate the carotid body. The concept behind the "mitochondrial hypothesis" of O₂ sensing is that the lack of O₂ would reduce the activity of cytochrome c oxidase in complex IV, thus resulting in mitochondrial depolarization and Ca²⁺ release (72). This form of mitochondria involvement in O₂ sensing lost support after the discovery that cell responsiveness to low PO₂ requires membrane depolarization and Ca²⁺ entry through plasmalemmal voltage-gated channels (see Ref. 37). Nevertheless, the interest in mitochondria has resurged in the past years owing to studies testing the redox model of acute O₂ sensing (1, 34, 43, 81). Mitochondria consume almost all available O₂ and are major sources of due to inefficient transfer of electrons along the respiratory chain. Although there is no general agreement on whether hypoxia decreases or increases cell ROS production, it has recently been proposed for pulmonary arterial myocytes that hypoxia is sensed by the decrease in the velocity of electron transfer from cytochrome c to O₂, thus leading to accumulation of ETC intermediates in the reduced state and the production of ROS. It is thought that radicals are preferentially generated at the semiubiquinone site, where an electron can leak out to produce (34, 79). This view contrasts with earlier observations indicating that hypoxia shifts pulmonary VSMCs to a more reduced state (1, 84). Although participation of mitochondria in the response to hypoxia of arterial pulmonary myocytes cannot be discarded (1, 34, 43, 81), the assumption that these organelles have a general role in O₂ sensing is questioned by numerous experimental findings. O₂-sensitive maxi-K⁺ channels of rat glomus cells respond to PO₂ changes independently of redox modification (59), and reduction of K⁺ currents by hypoxia is maintained in airway chemoreceptor cells devoid of mitochondria or after mitochondrial inhibition (65). In whole carotid bodies, the reduced (GSH)-to-oxidized (GSSG) glutathione ratio remains unchanged during exposure to hypoxia despite the fact that this quotient increases after incubation of carotid bodies with N-acetylcysteine, a precursor to GSH and ROS scavenger (64). In addition, it has been shown that hypoxia responsiveness of intact glomus cells is unaffected by the complete blockade of the mitochondrial electron flow with saturating concentrations of ETC inhibitors acting at the different mitochondrial complexes. Interestingly, rotenone selectively occludes responsiveness to hypoxia, an effect not mimicked by other complex I inhibitors and unaltered by feeding electrons through complex II with succinate (48). Therefore, it seems, that although a rotenone-inhibited molecule is essential for carotid body O₂ sensing, this phenomenon is independent of mitochondrial electron flow. Discrete rotenone binding sites outside mitochondria have not been reported, but the existence of cytosolic aggregates of preassembled complex I proteins of unknown function has been documented (see Ref. 48). Rotenone has a relatively high affinity (in the nM range) for the carotid body O₂-sensing machinery; therefore, it could be used as a probe to investigate its location and nature in glomus cells.

O₂-Dependent Hydroxylases, HIF, and Acute O₂ Sensing

Another possible form of acute O₂ sensing that has recently been explored involves O₂-dependent prolyl and asparaginyl hydroxylases, which are known to regulate the activity of hypoxiainducible transcription factors (mainly HIF isoforms 1 and 2) (42). Protein hydroxylation does not seem, however, to participate directly on acute O₂ sensing, as incubation of carotid body slices with dimethyloxalylglycine, a membrane-permeant competitive inhibitor of oxoglutarate that completely inhibits hydroxylases and induces the expression of O₂-sensitive genes (16), does not alter the responsiveness of glomus cells to hypoxia (47). However, HIFs appear to be necessary for setting the appropriate level of expression of the O₂-sensing machinery in carotid body cells and pulmonary myocytes. Heterozygous HIF-1^+/- mice, with apparently normal carotid body histology, have impaired responses to low PO₂ and adaptability to chronic hypoxia (33). Similarly, in HIF-1^+/- mice, the changes of pulmonary arterial myocyte membrane potential and K⁺ channel density induced by chronic hypoxia are blunted (67).

	EFFECTS OF CHRONIC HYPOXIA ON ION CHANNEL GENE EXPRESSION

TOP ABSTRACT ACUTE RESPONSES TO HYPOXIA... MECHANISMS OF O2 SENSING... EFFECTS OF CHRONIC HYPOXIA... PATHOPHYSIOLOGY ASSOCIATED WITH... FUTURE RESEARCH DIRECTIONS ACKNOWLEDGMENTS REFERENCES

 
Despite the progress in the understanding of the role of ion channels in the acute cellular responses to lowering O₂ tension, the participation of these proteins in the adaptive long-term changes induced by chronic hypoxia has not been studied in detail. It is known that prolonged hypoxia downregulates various Kv channel genes in pulmonary artery smooth muscle cells (55, 69, 80). Chronic hypoxia also reduces K⁺ current amplitude (26, 86) but increases the density of Na⁺ and Ca²⁺ channels in carotid body glomus cells (29, 70). Recently, detailed molecular biology and electrophysiological studies have shown that T-type Ca²⁺ channels are upregulated by hypoxia in PC12 cells and possibly in other tissues (16). A five- to eightfold increase in the level of the T-type subunit 1H mRNA is found in PC12 cells when exposed to hypoxia (20 Torr), and mRNA induction is paralleled by an increase in the density of T-type Ca²⁺ currents (Fig. 3, A–D). These observations have suggested that upregulation of T-type Ca²⁺ channels by hypoxia may contribute to cellular functions susceptible of modulation by low O₂ concentration, such as cellular excitability, differentiation, growth, and proliferation. T-type Ca²⁺ channel gene induction is also stimulated by desferroxamine, cobalt, or dimethyloxalylglycine. These compounds mimic hypoxia by inhibiting oxygen-, Fe²⁺-, and oxoglutarate-dependent dioxygenases that under normoxic conditions hydroxylate specific proline and asparagine residues in HIF before its degradation (42). In addition, it has been shown that stabilization of HIF or induction of 1H mRNA by hypoxia is blocked when the cells are incubated with HIF antisense oligonucleotides (16). The involvement of HIF in the hypoxic upregulation of the 1H Ca²⁺ channel suggested by these experiments is further supported by the presence of hypoxia responsive elements (HIF to DNA binding sites) in the 5'-flanking region of the 1H gene (Fig. 3E). This promoter region is highly conserved among mammals, with more than 71% similarity between rodents and humans and 93% similarity between rats and mice. These results indicate that T-type Ca²⁺ channels, and possibly other ion channels, are part of the gene program developed under chronic hypoxia. The data summarized in Fig. 3 represent the first example of an ion channel gene whose expression, similar to erythropoietin and other classical O₂-sensitive genes, is regulated by the O₂-sensitive hydroxylase-HIF pathway (9, 42, 66).

View larger version (43K): [in this window] [in a new window]   Fig. 3. Upregulation by chronic hypoxia of T-type Ca2+ channel gene (1H). A: Northern blot analysis of 1H mRNAs from cells exposed to either normoxia (21% oxygen, time 0) or hypoxia (3% oxygen) for the indicated periods of time. The levels of the cyclophilin (CP) and tyrosine hydroxilase (TH) mRNAs were analyzed to normalize the amount of RNA in each line and to check for the ability of PC12 cells to induce the expression of an O2-sensitive gene. B: average fold induction of 1H mRNA levels expressed as -fold change ± SE in the hypoxic samples compared with the normoxic sample (time 0). Inset: example of a PCR experiment (30 cycles) where -actin was used to normalize the amount of RNA in each line. N, normoxic; H, hypoxic. C and D: electrophysiological identification of slowly deactivating T-type channels in PC12 cells. Current density due to T-type Ca2+ channel activity increased 2.3-fold on exposure to hypoxia (3% oxygen) for 18–24 h. E: alignment of the nucleotide sequences of the rat, mouse, and human 1H 5'-flanking region containing 6 putative hypoxia-inducible factor (HIF) consensus DNA binding sites. The core motifs are in bold face and upperlined by arrows to indicate the plus (rightward arrow) or minus (leftward arrow) DNA strand location. Note that 2 putative HIF binding sites (indicated by letters of larger size) are conserved among the 3 species. (Modified from Ref. 16.)

	PATHOPHYSIOLOGY ASSOCIATED WITH ION CHANNEL-DEPENDENT O2 SENSING

TOP ABSTRACT ACUTE RESPONSES TO HYPOXIA... MECHANISMS OF O2 SENSING... EFFECTS OF CHRONIC HYPOXIA... PATHOPHYSIOLOGY ASSOCIATED WITH... FUTURE RESEARCH DIRECTIONS ACKNOWLEDGMENTS REFERENCES

 
Primary Alterations of Acute O₂ Sensing

There are several human diseases that seem to be related to primary alterations of the acutely responding O₂-sensitive cells. Some cases of congenital central hypoventilation syndrome (CCHS) appear without alterations in central respiratory centers but with marked decrease in the number of glomus cells and hypoplasia of carotid bodies despite a two- to threefold increase of sustentacular cells (12). In this same study, compensatory hyperplasia of the neuroepithelial bodies of the lung was also observed. In 10–20% of patients, CCHS is associated with Hirschsprung disease, thus raising the possibility that the RET protooncogene, altered in Hirschsprung disease, participates in the mechanisms of O₂ sensing. Interestingly, RET is part of the multicomponent receptor complex of the glial cell line-derived neurotrophic factor (GDNF); in addition, both RET and GDNF are highly expressed in adult carotid bodies (76). Therefore, GDNF activation of RET is probably required for the maintenance of the O₂ sensitivity of glomus cells. Increased sustentacular cell number (28) and decreased carotid body size (45) have also been reported for some cases of sudden infant death syndrome (SIDS). Unexpected sudden death has been reported after bilateral carotid body denervation in humans and animals (17, 73), and infants prone to apnea have altered responses to mild hypoxia (6). Carotid body dysfunction in these syndromes could be the result of a primary alteration of either the O₂ sensor or the ion channels acting as effectors. Chronic exposure to hypoxia or application of chemostimulants induce glomus cell overexcitability, increased Ca²⁺ entry, and carotid body hyperplasia (29, 48, 86). Thus glomus cell hypoexcitability could underlie the hypoplasia observed in CCHS and SIDS. Perrin et al. (54) reported in patients affected by SIDS the presence of higher carotid body dopamine content than in normal children. This could also be the cause of carotid body hypoexcitability, as it is known that dopamine inhibits Ca²⁺ currents in glomus cells (5).

Alteration of O₂-sensitive K⁺ channels could also participate in the pathophysiology of primary pulmonary hypertension, a condition characterized by increased resistance of the fine branches of the pulmonary artery. VSMCs taken from small pulmonary arteries of patients with primary pulmonary hypertension appear to be depolarized and to have higher cytosolic [Ca²⁺] levels relative to cells from patients with secondary pulmonary hypertension (88). In addition, several anorexic drugs (aminorex, fenfluramine, and others), known to produce pulmonary hypertension, have been shown to inhibit macroscopic K⁺ currents in pulmonary arterial smooth muscle (83). A direct link between maxi-K⁺ channels and pulmonary hypertension has been demonstrated in newborn lambs (46). Interestingly, it has recently been reported that in vivo transfer of Kv1.5 channels reduces pulmonary hypertension and restores HPV in chronically hypoxic rats (57).

Chronic Hypoxia and Modifications of Ion Channel Gene Expression

Different forms of chronic hypoxia (sustained or intermittent) cause alterations of various O₂-sensitive tissues (58). Maintained reductions of O₂ tension (either in high altitude or in cages for experimental animals) induce a marked carotid body hypertrophia and blunted response to low PO₂. It has been reported that glomus cells from chronically hypoxic carotid bodies are more excitable, due to the overexpression of Na⁺ and Ca²⁺ channels, but they also have reduced voltage-dependent K⁺ current amplitude (26, 29, 70, 86). Intermittent hypoxia is known to cause hypertension, secondarily to activation of arterial chemoreceptors and subsequent sympathetic stimulation (19). However, it is also possible that hypoxia causes alteration in the expression of channels that regulate smooth muscle excitability in the systemic vasculature. In the pulmonary arterial tree, chronic hypoxia reduces the amplitude of macroscopic K⁺ currents (69) and downregulates various voltage-gated K⁺ channels (55, 80). As described in the preceding section, the expression of T-type Ca²⁺ channel genes is increased by hypoxia in PC12 and other cell types (16). Given the broad distribution of these channels, they probably have a major role in cell adaptation to chronic hypoxia.

	FUTURE RESEARCH DIRECTIONS

TOP ABSTRACT ACUTE RESPONSES TO HYPOXIA... MECHANISMS OF O2 SENSING... EFFECTS OF CHRONIC HYPOXIA... PATHOPHYSIOLOGY ASSOCIATED WITH... FUTURE RESEARCH DIRECTIONS ACKNOWLEDGMENTS REFERENCES

 
Over the past decade, we have witnessed a rapid development and maturation of the field of O₂ sensing due to the identification and characterization of effector molecules, particularly ion channels and transcription factors. A major recent advance has been the discovery of the O₂-dependent hydroxylases that regulate the stabilization and transcriptional activity of HIF (42). Regarding the role of ion channels in O₂ sensing, a significant contribution has been the demonstration that, as the classical O₂-sensitive genes, they are also regulated by the HIF signaling pathway and therefore are part of the gene program developed under chronic hypoxia (16, 66). The study of ion channel-encoding O₂-sensitive genes will surely receive higher attention in the near future. Although the present experimental work further supports the notion that O₂-regulated ion channels participate in the acute cellular responses to hypoxia, there are several unresolved pivotal questions pertaining to the nature of the O₂ sensors and the mechanisms of interaction of the sensors with the ion channels. We have summarized in this review recent work that, in our view, helps to distinguish between the mechanisms that need to be explored further and those that lack experimental support. It is possible that acute O₂ sensing does not utilize a single mechanism but that different O₂ sensors are expressed in the various hypoxia responsive cells. Nevertheless, new experimental work is urgently needed to fully characterize the involvement of ion channels in the hypoxia signaling pathway. The combination of biophysical, molecular biology, and pharmacological techniques applied to in vitro preparations and animal models are experimental approaches that are already yielding important results. These techniques are helping to clarify the critical role of ion channels in hypoxic pulmonary hypertension (57, 80, 83, 88). Similarly, rotenone, a drug that selectively occludes sensitivity to hypoxia of carotid body glomus cells (48), could be a useful tool to search for the location and nature of the carotid body O₂ sensor. Finally, it can be expected that this basic knowledge will have a medical impact. Ion channels and other O₂-sensitive effectors are involved in vasomotor and cardiorespiratory control, and localized lacks of O₂ are critical in the pathogenesis of major causes of mortality. Therefore, amplification or inhibition of adaptive responses to hypoxia is a promising pharmacological strategy that may result in effective therapies for human diseases.

	ACKNOWLEDGMENTS

TOP ABSTRACT ACUTE RESPONSES TO HYPOXIA... MECHANISMS OF O2 SENSING... EFFECTS OF CHRONIC HYPOXIA... PATHOPHYSIOLOGY ASSOCIATED WITH... FUTURE RESEARCH DIRECTIONS ACKNOWLEDGMENTS REFERENCES

 
The authors thank María García-Fernández for comments on the manuscript.

GRANTS

J. López-Barneo is a recipient of the "Ayuda a la Investigación 2000" of the Juan March Foundation.

	FOOTNOTES

 

Address for reprint requests and other correspondence: J. López-Barneo, Laboratorio de Investigaciones Biomédicas, Edificio de Laboratorios, 2^a planta, Hospital Universitario Virgen del Rocío, Avenida Manuel Siurot s/n, E-41013 Sevilla, Spain (E-mail: Jose.L.Barneo.sspa{at}juntadeandalucia.es).

	REFERENCES

TOP ABSTRACT ACUTE RESPONSES TO HYPOXIA... MECHANISMS OF O2 SENSING... EFFECTS OF CHRONIC HYPOXIA... PATHOPHYSIOLOGY ASSOCIATED WITH... FUTURE RESEARCH DIRECTIONS ACKNOWLEDGMENTS REFERENCES

 

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