© 2000 American Heart Association, Inc.
Editorials |
Are Kv Channels the Essence of O2 Sensing?
From the Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid y CSIC; Departamento de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, Valladolid, Spain.
Correspondence to M. Teresa Pérez-García, Universidad de Valladolid, Departamento de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, c/Ramón y Cajal 7, 47005 Valladolid, Spain. E-mail tperez{at}ibgm.uva.es
Key Words: Kv channels • hypoxia • O2 sensor
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Introduction |
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 Top Introduction References |
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With the exception of anaerobes, organisms depend on oxygen for the production of energy and for biosynthetic reactions. Therefore, cells, tissues, and organisms must be able to sense and respond to changes in the oxygen concentration of their environment. The response of mammalian cells to hypoxia is crucial for their survival, allowing cells to cope with a low-oxygen environment. There are, however, specialized cells located in chemosensory organs (carotid bodies, pulmonary neuroepithelial bodies, and pulmonary artery smooth muscle among others) whose responses to hypoxia are unique, differing both quantitatively and qualitatively from the general self-defense reaction to hypoxia observed in other cell types. The specific hypoxic response of these chemosensitive cells is fast (seconds to minutes), has a lower threshold, requires an increase in their metabolic activity, and leads to changes in their excitability, contractility, and/or secretory activity. All of these features are specializations designed to prevent hypoxia in the entire organism and, thus, to maintain homeostasis.
The physiological role of these specialized responses is well characterized, but the molecular mechanisms of O2 sensing and their transduction into an adaptive response in chemoreceptor cells is poorly understood. Over the past decade, it has been well established that modulation of ion channel activity by changes in oxygen levels contributes to the chemoreceptor cell response to low PO2. Since the pioneer description of a low PO2-modulated K+ current in rabbit carotid body chemoreceptor cells1 many other O2-sensitive K+ channels have been identified in chemosensory preparations.2 The high degree of kinetic and pharmacological diversity among O2-sensitive K+ channels has focused our interest toward determining the structural requirements for O2 sensing. Several K+ channel genes expressed in some of the cell types sensitive to hypoxia have been identified, and for some of them, low PO2 modulation has been studied in heterologous expression systems. However, there are conflicting reports with respect to which of these channels contributes to the native O2-sensitive K+ currents. Different genes can produce K+ channels with similar electrophysiological properties. In addition, K+ channels can form heterotetrameric complexes and/or associate with auxiliary modulatory subunits that could confer O2 sensitivity to the resulting channel. Determination of the molecular constituents of the O2-sensitive K+ currents in native tissues is a relevant issue, not only to provide a physiological meaning to the reported O2 modulation of cloned channels expressed in heterologous systems3 4 5 6 but also to understand the molecular mechanisms of O2 detection in hypoxia-sensitive tissues.
The study presented by Osipenko et al7 in this issue of Circulation Research is an important step in this direction. These authors investigate the effects of hypoxia on several recombinant Kv1 channels previously described in pulmonary artery smooth muscle (PASM) as well as Kv3.1, with kinetics and pharmacological properties similar to the PASM native O2-sensitive currents. They report that (1) recombinant Kv3.1 is modulated by hypoxia through a membrane-delimited mechanism, (2) Kv3.1 is expressed in PASM cells, and (3) Kv3.1 appears to contribute to the hypoxic inhibition of delayed rectifier K+ currents in these cells.
From our perspective, this report represents a relevant contribution to the study of oxygen sensing for two main reasons. First, it shows an approach adequate for identification of a putative O2-sensitive K+ channel, by moving from the modulation by hypoxia of a recombinant channel back to its physiological context, the role of this channel in the response to low PO2 of the native cells. Second, it demonstrates that hypoxic inhibition of the recombinant Kv3.1 channels is retained in excised membrane patches, pointing to a membrane-delimited mechanism as the origin of hypoxic responses. The importance of this latter finding deserves additional comment.
Kv3.1 represents a new O2-sensitive K+ channel described in PASM cells. However, other Kv channels present in these cells have also been implicated in their response to low PO2, including the Kv2.1/Kv9.3 heteromultimer, the homomeric Kv1.2, or the heteromeric Kv1.2/Kv1.5 (see Reference 7 and references therein). If we add to this picture the fact that both the expression and the functional contribution to the hypoxic response of different Kv channels in PASM seem to exhibit species-related differences, we are far from understanding the complex molecular basis of O2 sensing in PASM cells. We can add more entropy to this description by pointing out that the same situation (several O2-sensitive K+ channels with species-related differences in their molecular identity) has also been found in chemoreceptor cells of the carotid body.2 Finally, there are also non-K+ channels that respond to hypoxia. In this context, it is worth speculating about the real essence of O2 sensing by ionic channels, looking for a possible common link between hypoxia and the distinct O2-sensitive K+ channels in different chemosensory tissues. Indeed, the mechanism by which hypoxia modulates channel activity has been a point of discussion during the last few years. Two questions are of paramount interest: (1) Does the effect of hypoxia on O2-sensitive K+ channels require intracellular mediators? and (2) If low PO2 can modulate O2-sensitive K+ channels in the absence of cytoplasmic factors, is the O2 sensor the channel itself or a closely associated molecule? As mentioned, the present study7 provides a clear answer to the first question, demonstrating that the hypoxic inhibition of Kv3.1 channels is maintained in cell-free patches in the absence of potential intracellular mediators. This has also been observed for other recombinant O2-sensitive K+ channels,6 as well as for native K+ currents in chemosensitive tissues.8 9 In contrast (or perhaps in addition) to this clearly membrane-delimited mechanism, several cytosolic factors have been implicated in the hypoxic modulation of K+ channels (see Reference 10 and references therein). However, although this redox modulation may well be important, a conclusive link between hypoxia and the redox state of the cell has not been demonstrated.
Regarding the second question raised, ie, the identity of the O2 sensor, there are two obvious possibilities. First, the K+ channels themselves function as O2-sensing devices, and second, there is an O2-sensing molecule closely associated with the membrane that is capable of interacting with only certain kinds of K+ channels, modifying their activity in the presence of low levels of O2. This latter hypothesis certainly provides a unifying explanation of the apparent diversity. As mentioned above, the biochemical adaptations to hypoxia constitute a universal response. So, it is plausible to think of the existence of a universal O2 sensor that can couple to different effectors in the different cell types thereby providing cell-specific responses. From this point of view, Kv channels are clearly not O2-sensing devices. They are just the first effectors in the chemotransduction cascade. In any case, with the present report,7 the spectrum of Kv channels modulated by low O2 widens a bit more. The literature does not agree yet about which Kv channels are O2 sensitive and, among them, which are functionally relevant. Nevertheless, it is clear that there is not a single "O2-sensitive" channel, and that O2 sensitivity is not a common feature of all Kv channels. Why channels so similar in their molecular structure behave so differently when exposed to a low-oxygen environment is a mystery we do not yet understand. The hypothesis of a general sensor interacting with different channels, directly or through auxiliary subunits, is appealing. It could explain why recombinant Kv1 channels seem to be O2 sensitive in some expression systems but not in others (see Reference 7 and references therein) or why the molecular identity of the O2-sensitive K+ current is so different among different species. The existence of a putative sensor is also supported by the observation that hypoxic inhibition of both native and recombinant O2-sensitive K+ channels can be reverted by carbon monoxide.6 11 Because the only known targets of carbon monoxide in biological systems are metalloproteins, particularly hemoproteins, the observation that carbon monoxide is able to interact with this putative O2 sensor, replacing O2 and preventing the inhibition of K+ currents, strongly suggests that the intrinsic O2 sensor could be a hemoprotein.
Speculation is a necessary first step in the pursuit of knowledge, but final answers always require well-designed experimental settings. O2 sensing and Kv channels are still puzzling partners, despite the considerable amount of work performed in the last few years. The approach by Osipenko et al,7 combining the study of physiological responses in native tissues with the study of expression of recombinant channels in heterologous systems, will certainly bring valuable new information to bear in solving this mystery.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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- Patel AJ, Lazdunski M, Honore E. Kv2.1/Kv9.3, a novel ATP-dependent delayed-rectifier K+ channel in oxygen-sensitive pulmonary artery myocytes. EMBO J. 1997;16:6615–6625.[Medline] [Order article via Infotrieve]
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Fearon IM, Palmer AC, Balmforth AJ, Ball SG, Varadi G,
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1C subunits
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[Abstract/Free Full Text] -
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Gonzalez C. Kvß1.2 subunit coexpression in HEK293 cells confers
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[Abstract/Free Full Text] -
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