EDITORIAL FOCUS
Oxygen-sensitive K+ channel(s): where and what?

Jason X.-J. Yuan

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Diego, California 92103


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HYPOXIC PULMONARY VASOCONSTRICTION (HPV) serves as an important regulatory mechanism to match perfusion to ventilation by directing blood flow away from poorly ventilated regions of the lung to ensure maximal oxygenation of the venous blood. Persistent HPV, however, causes pulmonary hypertension that may lead to right heart failure in patients with obstructive pulmonary diseases and congenital heart defects as well as in dwellers residing in high-altitude areas. The cellular and molecular mechanisms involved in HPV have been extensively investigated since 1876 when HPV was first observed, but the precise sequence of events by which hypoxia causes pulmonary vasoconstriction is still unclear. The observations that hypoxia causes vasoconstriction in endothelium-denuded pulmonary artery (PA) rings (29, 48, 60) and induces contraction in single PA smooth muscle cells (SMCs) (28, 34, 55, 62) suggest that HPV is an intrinsic property of the pulmonary vasculature and that the mechanism of HPV involves direct oxygen sensing by PASMCs. The full in vivo expression of HPV, however, might involve an interaction of PASMCs with the endothelium (23, 48).

A rise in cytoplasmic free Ca2+ concentration ([Ca2+]cyt) in PASMCs is a major trigger for pulmonary vasoconstriction. [Ca2+]cyt is increased by Ca2+ influx through Ca2+-permeable channels in the plasma membrane and/or by Ca2+ mobilization from intracellular Ca2+ stores (e.g., sarcoplasmic/endoplasmic reticulum). There are at least three classes of Ca2+-permeable channels in PASMCs: 1) voltage-dependent Ca2+ channels (VDCCs), 2) receptor-operated Ca2+ channels, and 3) store-operated Ca2+ channels. By governing Ca2+ influx via VDCCs, the membrane potential (Em) plays a critical role in regulating [Ca2+]cyt and vascular tone (35). One of the well-defined mechanisms in eliciting HPV involves the membrane depolarization-mediated opening of VDCCs, which subsequently increases [Ca2+]cyt in PASMCs and induces pulmonary vasoconstriction (18, 27). Indeed, blockade of Ca2+ channels with nifedipine and verapamil inhibits and removal of external Ca2+ abolishes the hypoxia-induced pulmonary vasoconstriction and contraction in single PASMCs (28, 32, 51, 60). In contrast, activation of VDCCs with BAY K 8644 potentiates HPV (31).

The Em is primarily controlled by activity of the Na+-K+-ATPase and K+ channels in the plasma membrane. A decrease in K+ currents through plasmalemmal K+ channels (due to blockade of the channel conductance and/or downregulation of the channel expression) causes membrane depolarization, whereas an increase in K+ currents causes membrane hyperpolarization. Functionally, K+ channels are classified into five families: 1) voltage-gated K+ (KV) channels, 2) Ca2+-activated K+ channels, 3) ATP-sensitive K+ channels, 4) inward rectifier K+ channels, and 5) voltage-insensitive background K+ channels (20, 22). When based on molecular structure, K+ channels are categorized into three families: 1) channels with one-pore and six-transmembrane domains (e.g., KV and Ca2+-activated K+ channels), 2) channels with one-pore and two-transmembrane domains (e.g., ATP-sensitive K+ and inward rectifier K+ channels), and 3) channels with two-pore and four-transmembrane domains [e.g., voltage-insensitive background K+ channels, like weakly inward rectifying K+ channels (TWIK)] (20, 22).

Transmembrane K+ current through KV channels [IK(V)] is thought to primarily determine the level of Em in PASMCs (13, 44, 58). Thus Em is directly related to the level of whole cell IK(V), which is determined by IK(V) = N × i × Po, where N is the number of membrane KV channels, i is the single-channel KV current, and Po is the steady-state open probability of the KV channel. When KV channels close (i or Po is decreased) or KV channel expression declines (N is decreased), Em becomes less negative and depolarization occurs as a result of decreased whole cell IK(V). When KV channels open (i or Po is increased) or KV channel expression rises (N is increased), the Em becomes more negative and hyperpolarization occurs as a result of increased IK(V). Due to the important role of K+ channel activity in regulating the Em, [Ca2+]cyt, and vascular tone, McMurtry et al. (33) proposed almost 20 years ago that HPV might be induced by inhibition of membrane K+ channels.

In 1988, Lopez-Barneo et al. (24) first described a hypoxia-inhibited K+ current in rabbit carotid body chemoreceptor cells, which provoked many investigators to study the effect of hypoxia on K+ currents in PASMCs. Several years later, Post et al. (45) and Yuan et al. (59) provided direct evidence that acute hypoxia did indeed decrease K+ currents and caused membrane depolarization in PASMCs isolated from canines and rats. Since then, there have been many studies attempting to characterize the electrophysiological properties and specify the molecular identities of the so-called oxygen-sensitive K+ channels in oxygen-sensitive cells such as carotid body chemoreceptor cells (26), central neurons (17), pulmonary neuroepithelial cells (15, 36, 53), pheochromocytoma (PC12) cells (5, 6), and PASMCs (1-3, 19, 37, 38, 40, 43, 44, 49, 50, 54, 59). Based on what we know so far, KV channels appear to be a top candidate as the oxygen-sensitive K+ channels in PASMCs (1-3, 19, 37, 38, 40, 43, 44, 49, 50, 54, 59), although other types of K+ and Ca2+ channels are also regulated by hypoxia (17, 25, 41).

At the molecular level, KV channels are heteromeric or homomeric tetramers composed of the pore-forming alpha -subunits and the cytoplasmic regulatory (auxiliary) beta -subunits (20). Using RT-PCR and immunoblot analyses, investigators have identified a number of KV channel alpha - and beta -subunits expressed in isolated pulmonary arteries and in PASMCs from humans and animals (e.g., rat, rabbit, canine, and cow; Table 1) (3, 7-9, 19, 38, 40, 52, 61). Characterization of cloned KV channels indicates that the native KV channels are most likely heteromultimers formed by both alpha - and beta -subunits in a 1:1 molar ratio. In other words, each alpha -subunit associates with a beta -subunit to form alpha 4beta 4 heteromultimers in native Shaker-related KV channels (39). The KV channel beta -subunits tightly bind to the cytoplasmic side of the alpha -subunits through an NAB domain (57). The major function of the beta -subunits when associated with the alpha -subunits includes conferring rapid inactivation onto the non- or slowly inactivating KV channel alpha -subunits (e.g., Kv1.1, Kv1.2, and Kv1.5) (46) and blocking the alpha -subunits as an open channel blocker (10). Which of these KV channel alpha - and/or beta -subunits form the oxygen-sensitive KV channels in vivo that are responsible for HPV has been studied extensively during last 5 years.

                              
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Table 1.   KV channel alpha - and beta -subunits expressed in pulmonary vasculature and channels potentially involved in oxygen sensing

A number of studies have been focused to determine the sensitivity to hypoxia of the channels formed by recombinant KV channel subunits in heterologous expression systems, including Xenopus oocytes, mouse L-cell line, Chinese hamster ovary cells, rat adrenal PC12 cells, COS-7 cells, and HEK-293 cells (7, 25). The potential candidates of the KV channel alpha -subunits that could form oxygen-sensitive, homomeric, or heteromeric channels have been demonstrated to include Kv1.2 (5, 19), Kv1.5 (2, 3), Kv1.2/Kv1.5 (19), Kv2.1 (5, 25, 40), Kv2.1/Kv9.3 (19, 40), Kv3.1b (38), Kv3.3 (24, 53), and Kv4.2/Kvbeta 1.2 (42) (Table 1). Acute hypoxia (<3 min) significantly reduces the K+ currents generated by these homomeric or heteromeric channels, and the hypoxic sensitivity of these channels appears to be independent of the expression systems. Furthermore, chronic exposure to hypoxia for 1-2 days has been demonstrated to downregulate the expression of KV channel alpha -subunits (e.g., Kv1.1, Kv1.2, Kv1.5, Kv2.1, Kv4.3, and Kv9.3) and reduce whole cell IK(V) in PASMCs (43, 50, 54). These observations indicate that acute (<= 3-min) and chronic (>= 24-h) hypoxia both decrease the activity of KV channels, likely via different mechanisms and targeting on different channel subtypes.

In PASMCs and other oxygen-sensitive cells, hypoxia alters the redox status as determined by the ratio of the reduced to the oxidized forms of glutathione (GSH/GSSG) and/or nicotinamide adenine dinucleotide phosphate (NADPH/NADP+ or NADH/NAD+) and shifts the cells to a more reduced state (1, 56). There are 8-14 cysteine residues in each of the KV channel alpha -subunits (e.g., Kv1.1, Kv1.2, Kv1.5, and Kv2.1), and 5-7 cysteine residues in each of the beta -subunits (e.g., Kvbeta 1.1 and Kvbeta 1.2). Cysteine residues in KV channel alpha - and beta -subunits are sensitive to redox change; therefore, both the alpha - and beta -subunits can be potentially regulated by the hypoxia-mediated redox change.

Since 1992 when Parcej et al. (39) first described a KV channel beta -subunit, there are at least four families of beta -subunits that have been cloned and described in mammals and humans: 1) Kvbeta 1 (Kvbeta 1.1, Kvbeta 1.2, and Kvbeta 1.3), 2) Kvbeta 2 (Kvbeta 2.1 and Kvbeta 2.2), 3) Kvbeta 3 (Kvbeta 3.1), and 4) Kvbeta 4 (Kvbeta 4.1) (12, 14). Based on the gene sequence (4, 30) and crystal structure (16), the KV channel beta -subunits are similar to the redox-sensitive NAD(P)H-dependent oxidoreductase proteins. In 1994, Rettig et al. (46) identified a cysteine residue in the beta -subunit that is sensitive to oxidation and critical in binding the NH2-terminal inactivating domain in the beta -subunit to the inner mouth of the channel pore formed by the alpha -subunits. When the cysteine residue is reduced, the NH2-terminal inactivating domain occludes the opened channel pore and the KV channels inactivate rapidly. In contrast, when the cysteine residue is oxidized, the inactivating domain cannot bind to the channel pore and the KV channels do not inactivate or slowly inactivate (46). Thus the beta -subunits have been demonstrated to be a redox sensor, which couples cellular redox status to KV channel function (16). Indeed, coexpression of Kvbeta 1.2 subunit confers oxygen sensitivity to Kv4.2 in HEK-293 cells (42), whereas reducing agents affect KV channel activity via the beta -subunits (46).

HPV occurs predominantly in small resistance pulmonary arteries. Therefore, if KV channel alpha - and beta -subunits are responsible for HPV, the expression of these subunits as well as the function of KV channels should be greater in PASMCs from resistance pulmonary arteries than cells from conduit pulmonary arteries. To this end, Coppock and Tamkun (8) compared the protein expression of various KV channel alpha - and beta -subunits between resistance and conduit bovine pulmonary arteries using immunoblot analysis and immunohistochemistry. They found that the protein levels of Kv1.5 (~1.5-fold) and Kv3.1b (~12-fold) were significantly greater in PASMCs isolated from resistance pulmonary arteries than in cells from conduit pulmonary arteries, whereas Kv2.1 protein levels were comparable. The modest overexpression of Kv1.5 in resistance PA was also confirmed with immunocytochemistry. Interestingly, the protein expression of Kvbeta 1.1, Kvbeta 1.2, and Kvbeta 1.3 dramatically increased along the PA tree. The protein levels, determined by Western blot analysis, of these beta -subunits were three- to sixfold greater in PASMCs isolated from the fourth division of pulmonary arteries (with an external diameter of 1-2 mm) than cells isolated from conduit pulmonary arteries (with an external diameter of 25-30 mm). Immunohistochemical studies also showed a greater protein expression of Kvbeta 1.2 in resistance pulmonary arteries than in conduit pulmonary arteries. The differential expression of Kvbeta 1.1, Kvbeta 1.2, and Kvbeta 1.3 suggest that the auxiliary beta -subunits may play an important role in oxygen sensing in PASMCs (8).

Using total RNA isolated from freshly dissected rat pulmonary arteries and mesenteric arteries, Davies and Kozlowski (9) recently found that the mRNA expression of Kv1.2, Kv1.5, Kv2.1, Kvbeta 1.1, and Kvbeta 2.1 was similar between small and large pulmonary arteries, whereas the mRNA expression of Kv3.4 and Kv4.1 was significantly greater in small pulmonary arteries than in large pulmonary arteries. Furthermore, the mRNA levels of Kv1.2, Kv2.1, Kv9.2, and Kvbeta 1.1 were much higher in pulmonary arteries (both large and small) than in the mesenteric arteries. Qualitative differences in KV channel alpha - and beta -subunits in SMCs isolated from pulmonary arteries and systemic arteries (e.g., coronary and mesenteric arteries) have not thus far been observed, but the divergent responses of the pulmonary and systemic vasculatures to hypoxia have been well documented. The quantitative difference in mRNA expression of Kv1.2, Kv2.1, Kv9.2, and Kvbeta 1.1 between pulmonary arteries and mesenteric arteries does suggest that these channel subunits may have an important role in HPV (although it needs to be reconciled with immunoblot analysis). Whether these subunits form the native KV channels that are dominantly involved in the regulation of resting Em and why hypoxia only inhibits these homomeric and heteromeric KV channels in PASMCs but not in systemic arterial SMCs require further investigation.

The differential expression of KV channel beta -subunits (especially Kvbeta 1.1) in bovine PASMCs as indicated by Coppock and Tamkun (8) may provide an explanation for the differential hypoxic sensitivities of conduit and resistance pulmonary arteries. To confirm that the beta -subunits are the oxygen sensor responsible for HPV needs further study with the combined approaches of electrophysiology and molecular biology. The observations by Coppock and Tamkun provide us with a new concept in searching for the oxygen sensor and strongly suggest that the auxiliary proteins (e.g., beta -subunits) and the chaperones (e.g., K+ channel-associated protein) (21) of the pore-forming alpha -subunits as well as their heterologous assembly with different alpha -subunits may play a critical role in determining the oxygen or redox sensitivity of KV channels in PASMCs.

Using mice lacking Kv1.5, Archer et al. (2) recently provided compelling evidence that the alpha -subunit was also required in hypoxia-induced reduction of K+ currents and in HPV. They found that deletion of the Kv1.5 gene was associated with 1) an impaired HPV in isolated perfused lungs and in isolated PA rings, 2) a reduced sensitivity of whole cell IK(V) to hypoxia, and 3) a decreased sensitivity of the Em to hypoxia. These observations indicate that Kv1.5 is definitely involved in hypoxia-induced membrane depolarization and HPV (2, 3) and that function of the native oxygen-sensitive heteromeric KV channels (e.g., Kv1.5/Kv1.2, Kv1.5/Kvbeta 1.1, Kv1.5/Kvbeta 1.2, Kv1.5/Kvbeta 1.3, and/or Kv1.5/Kvbeta 3.1) in PASMCs relies on Kv1.5. Whether Kv1.5 is the oxygen sensor per se or is an effector subunit of an unknown oxygen sensor is still unclear and needs further investigation.

In summary, there are currently three schools of thought regarding where and what the oxygen sensor(s) is in hypoxia-mediated regulation of KV channels: 1) the pore-forming alpha -subunits per se are the oxygen sensor, 2) the auxiliary or chaperone proteins binding to the alpha -subunits are the oxygen sensor, and 3) an unknown molecule or protein complex (e.g., NADPH oxidase) senses oxygen tension and regulates the KV channel function by affecting either the alpha - or beta -subunits (17, 25, 53). The candidate for the oxygen sensor may be heterogeneous and should not be limited to the different channel subunits. The oxygen sensor responsible for HPV may include multiple membrane channels (e.g., K+ and Ca2+ channels), membrane receptors, NADPH oxidase (15, 53), and intracellular organelles (e.g., mitochondria and sarcoplasmic reticulum) (11, 54). Thus the oxygen sensor in PASMCs responsible for HPV would be better defined as an oxygen-sensing system in which multiple "oxygen sensors" coordinate with each other and transduce hypoxic signals to different "effectors" to ensure efficacy.

It has to be emphasized that HPV or the hypoxia-mediated increase in [Ca2+]cyt is not only due to the membrane depolarization-induced opening of VDCCs. Indeed, Robertson et al. (47) demonstrated that in rat intrapulmonary arteries, the membrane depolarization-mediated Ca2+ influx played a minor role in the transient phase I constriction of HPV and was not involved in the sustained phase II constriction. Under physiological conditions, the transmural pressure and oxygen tension in different segments of PA tree vary dramatically. This suggests that HPV may be caused by different mechanisms in different PA segments (e.g., conduit, resistance, and precapillary pulmonary arteries). Inhibition of KV channels (1, 37, 45, 59), mobilization of stored Ca2+ in the sarcoplasmic reticulum (11, 44), activation of voltage-independent Ca2+ channels (47), and generation of reactive oxygen species from mitochondria (55) may all participate in the development of HPV.


    ACKNOWLEDGEMENTS

I appreciate the helpful comments on this review by Dr. I. F. McMurtry.


    FOOTNOTES

Address for reprint requests and other correspondence: J. X.-J. Yuan, Dept. of Medicine, UCSD Medical Center, 200 W. Arbor Dr., San Diego, CA 92103-8382 (E-mail: xiyuan{at}ucsd.edu).


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Am J Physiol Lung Cell Mol Physiol 281(6):L1345-L1349
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