© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Is Kv channel inhibition a common path to hypoxic pulmonary vasoconstriction?
Department of Physiology and Biophysics, and National Research Laboratory for Cellular Signalling, Seoul National University College of Medicine, 28 Yonkeun-Dong, Chongno-Ku, Seoul 110-799, South Korea
* Corresponding author. Tel.: +82-2-740-8224; fax: +82-2-763-9667 earmye{at}snu.ac.kr
Received 3 May 2002; accepted 3 May 2002
See article by Hogg et al. [1] (pages 349–360) in this issue.
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1. Kv channels and hypoxic pulmonary vasoconstriction |
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 Top 1. Kv channels and... 2. Kv1.5 vs. Kv2.13. Do Kv channels...4. Other channels or...References |
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Hypoxic pulmonary vasoconstriction (HPV), a vasomotor mechanism that matches regional perfusion to ventilation, is initiated by depolarization of the membrane potential of pulmonary arterial smooth muscle cells (PASMC). There are still many debates as to which factor(s) is(are) responsible to induce membrane depolarization [2]. Voltage-gated potassium channel (Kv), calcium-activated potassium channel (KCa), release of intracellular calcium, change of intracellular redox potential or other factors are candidates. However, the most probable candidate for membrane depolarization so far is the inhibition of voltage-gated potassium channels (Kv) which leads to opening of voltage-gated calcium channels, and then to vasoconstriction [3]. The Kv channels conduct an outward current which is slowly inactivating, and which is blocked by the Kv inhibitor 4-aminopyridine (4-AP) but not by inhibitors of Ca2+- or ATP-sensitive K channels.
The Kv channel family is very diverse and nine families of Kv channels are recognized from cloning studies, each with subtypes. In addition, further diversification is afforded by heteromultimeric tetramerization and alternative splicing of some Kv channels [4]. At least seven Kv channel subfamilies mRNA were detected in pulmonary arterial smooth muscle (Kv1, Kv2, Kv3, Kv4, Kv5, Kv6, and Kv9). Among them, several candidate channels have been proposed to initiate HPV, based on electrophysiological and pharmacological similarities between their characteristics in expression systems and properties of the hypoxia-sensitive K+ currents in pulmonary arterial smooth muscle cells (e.g. Kv1.2, Kv1.5, Kv2.1 and Kv3.1b). Cloning and expression of homomeric Kv1.2, Kv1.5 and Kv2.1 channels revealed that they all display slowly inactivating or non-inactivating Kv currents that are sensitive to block by 4-AP. Both Kv1.2 and Kv1.5 have been shown to be charybdotoxin (CTX)-insensitive, whereas Kv2.1 shows some inhibition to low concentration of CTX [5]. It was recently shown that Kv3.1b channels are present in pulmonary arterial smooth muscle cells [6]. Although the hypoxic sensitivity of Kv3.1b has been shown in expression systems, its role in HPV is unknown. Kv3.1b channels display greater sensitivity to TEA than does the endogenous IK of pulmonary arterial smooth muscle cells. It is generally thought that Kv2.1 and Kv1.5 are strong candidate for the initiation of hypoxic depolarization of PASMC. Hogg et al. [1] showed again that Kv2.1 channels play a pivotal role in mediating HPV. They detected Kv2.1 channel mRNA using reverse transcription-polymerase chain reaction (RT-PCR) and Kv2.1 channel proteins with immunohistochemistry in small pulmonary arteries of the rat. Anti-Kv2.1 antibody within the pipette attenuated IKV by 67% at +50 mV and hypoxia in the presence of the antibody did not affect the magnitude of IKV.
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2. Kv1.5 vs. Kv2.1 |
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Top1. Kv channels and...2. Kv1.5 vs. Kv2.13. Do Kv channels...4. Other channels or...References |
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Different genes can produce Kv channels with similar electrophysiological properties. Hypoxic inhibition of Kv2.1 channel is established [1,7,8]. Hypoxia reversibly inhibited Kv2.1 current. However, the inhibition occurs usually at the depolarized region, not in the voltage range of physiological membrane potentials. The problem is worse in case of Kv1.5. The results depended upon the laboratories. Human and rat Kv1.5 were not inhibited by hypoxia [7]. On the other hand, HPV was impaired in mice lacking the voltage-gated potassium channel Kv1.5 [9]. Pulmonary arterial smooth muscle cells in mice lacking Kv1.5 had less hypoxia-sensitive IK than wild-type cells and depolarized less to hypoxia. However, there was still hypoxia-sensitive K current and membrane depolarization. This was associated with some residual HPV in isolated lungs from mice lacking the voltage-gated potassium channel Kv1.5 [9]. This residual HPV might come from Kv2.1 [1]. Further studies are needed using mice lacking both Kv1.5 and Kv2.1. In fact there were reports about heterotetramerization of Kv channel subfamilies. The Kv1.2/Kv1.5 and Kv2.1/Kv9.3 heterotetramers were inhibited by hypoxia [7,8]. The heteromeric channels are inhibited by hypoxia in the voltage range of the resting membrane potentials. Other heterotetramers of Kv channel subfamilies are expected to be shown as a candidate for HPV in the near future.
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3. Do Kv channels need O2 sensor? |
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Top1. Kv channels and...2. Kv1.5 vs. Kv2.13. Do Kv channels...4. Other channels or...References |
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Hypoxic inhibition of K channels has been shown to be a membrane-delimited process [10], which occurs in the pulmonary arterial smooth muscle itself [6]. While the Kv channels in pulmonary arterial smooth muscle cells are the effectors of HPV, it is uncertain whether they are intrinsically O2-sensitive or are under the control of an O2 sensor. Certain K channels are rich in cysteine, and respond to the local redox environment, tending to open when oxidized and close when reduced [11,12]. O2-responsive tissues may have unique oxygen sensors that provide the proximal signal linking pO2 to K+ channel gating. While HPV was shown to be impaired in mice lacking the voltage-gated potassium channel Kv1.5 [9], homomeric Kv1.5 channels are not sensitive to hypoxia when expressed in mouse L-cells [7], COS cells or MEL cells [6]. Currents recorded from cloned Kv2.1 channels were reversibly inhibited by hypoxia, but the hypoxic response was detected in 99 and 56% of cells examined when expressed in mouse L-cells [7] and COS-7 cells [8], respectively.
NADPH oxidase is present in phagocytes, pulmonary arterial smooth muscle cells, carotid body type 1 cells, neuroepithelial bodies, and endothelial cells. It includes a membrane-bound flavocytochrome containing two subunits, gp91 phox and p22 phox, and the cytosolic proteins p47 phox and p67 phox, which bind to the flavocytochrome to form the active enzyme complex. NADPH oxidase was suggested as the O2 sensor in pulmonary airway chemoreceptor [13]. Hypoxia (pO2=15–20 mmHg) reversibly inhibited K currents (46%) in wild type cells whereas hypoxia had no effect on K current in oxidase-deficient cells. However, O2 sensor in pulmonary arterial smooth muscle cells was preserved in mice lacking the gp91 phox subunit of NADPH oxidase [14]. Considering that there are other types of NADPH oxidase, further studies are needed for the roles of the other NADPH oxidases.
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4. Other channels or factors? |
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Top1. Kv channels and...2. Kv1.5 vs. Kv2.13. Do Kv channels...4. Other channels or...References |
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There are also non-Kv channels that respond to hypoxia in other O2-responsive tissues. (1) L-type Ca channel was modulated by redox agents and hypoxia when stably expressed in HEK cells [15]. (2) TASK-like background potassium channel was considered as a candidate for O2 sensor in rat arterial chemoreceptor cells [16]. (3) Large conductance Ca2+-dependent K channel was modulated by O2 in a membrane-restricted manner [17]. It might be fair not to rule out the other channels considering the roles of ion channels in mediating HPV. And also there are still many important questions (O2 sensor molecule, role of intracellular calcium release, and involvement of endothelium etc.) to be answered.
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References |
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Top1. Kv channels and...2. Kv1.5 vs. Kv2.13. Do Kv channels...4. Other channels or...References |
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- Hogg D.S., Davies S.R.L., McMurray G., et al. Kv2.1 channels mediate hypoxic inhibition of IKV in native pulmonary arterial smooth muscle cells of the rat. Cardiovasc Res (2002) 55:349–360.
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