KV2.1 channels mediate hypoxic inhibition of IKV in native pulmonary arterial smooth muscle cells of the rat

Hogg, Dayle S; Davies, Andrew R.; McMurray, Gordon; Kozlowski, Roland Z.

doi:10.1016/s0008-6363(02)00411-x

Cited by 29 publications

(18 citation statements)

References 38 publications

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“…In addition, the combination of anti-Kv1.5 and -Kv2.1 cause greater depolarization than either antibody alone in resistance PASMCs . This is consistent with previous publications that K + efflux through Kv1.X and Kv2.X channels are the primary determinant of the resting membrane Pulmonary diseases and K + -channels 93 potential in the resistant PASMCs (Patal et al, 1997;Hogg et al, 2002;Archer et al, 2004). Consistent with the electrophysiological data, protein expression of Kv1.5 are greater in resistance arteries .…”

Section: Regional Diversity Of Kv Channels In Pasmcssupporting

confidence: 93%

Patho-, physiological roles of voltage-dependent K+ channels in pulmonary arterial smooth muscle cells

Park

Firth

Han

et al. 2010

J. Smooth Muscle Res.

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In this review, we demonstrate the basic properties, modulation of, and pathological changes in voltage-dependent K + (Kv) channels that are expressed in pulmonary arterial smooth muscle cells (PASMCs). Pulmonary Kv channels are thought to play a crucial role in the maintenance of resting membrane potentials, and therefore the vascular tone of the pulmonary arteries. Although the molecular identity of pulmonary Kv channels is not clear, Kv1.1, Kv1.2, Kv1.5, Kv2.1, Kv9.3, and Kv3.1 subtypes are expressed in PASMCs. In addition, resistant PASMCs contain greater amount of Kv channels as compared to conduit PASMCs. This heterogenetic expression of Kv channels is consistent with regional differences in the contractile response to hypoxia. Similar to other K + channels, pulmonary Kv channels can also be modulated by several vasoconstrictors concomitant with the activation of protein kinase C (PKC). Alterations in Kv channel function have several additional and interrelated consequences, including the regulation of cell proliferation and apoptosis, which ultimately lead to pulmonary vascular remodeling. Increased pulmonary vasoconstriction in pulmonary arterial hypertension is attributable to decreased expression and activity of Kv channels in smooth muscle cells. Kv channels play a central role in the maintenance of cellular homeostasis and ion channels, and consequential signaling cascades. Therefore, Kv channels are potential therapeutic targets for the treatment of pulmonary vascular disease.

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Section: Regional Diversity Of Kv Channels In Pasmcssupporting

confidence: 93%

Patho-, physiological roles of voltage-dependent K+ channels in pulmonary arterial smooth muscle cells

Park

Firth

Han

et al. 2010

J. Smooth Muscle Res.

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“…19,20,43 Kv2.1 contributes to setting the resting E M in PASMCs and to HPV 19 ( Figure 8A). The current study suggests that Kv2.1 accounts for the portion of 4-APsensitive current that is correolide-insensitive.…”

Section: Archer Et Al Ionic Heterogeneity Explains Vascular Diversitymentioning

confidence: 99%

“…Hogg et al also used immunoelectropharmacology to demonstrate that antiKv2.1 inhibited normoxic I Kv (67% at ϩ50 mV) and reduced the hypoxia-responsive I K . 43 They did not assess the effects of anti-Kv1.5 and concluded that Kv2.1 plays a crucial role in HPV and in setting E M . The quantitative difference in the importance of Kv2.1 may relate to the dose and specificity of the Kv2.1 antibody used.…”

Section: Archer Et Al Ionic Heterogeneity Explains Vascular Diversitymentioning

confidence: 99%

“…17 Although they performed no molecular studies, the pharmacology suggested the TEA-sensitive Kv current was Kv2.1, and the exclusively 4-AP-sensitive current was Kv1.5, an interpretation consistent with previous publications. 19 Patch-clamp surveys of PASMC electrical phenotypes have revealed greater functional expression of L-type calcium channels 46 and Kv channels 7,17,43 in resistance PASMCs, and more BK Ca current in conduit PASMC. 7 In addition to this longitudinal diversity, phenotypically and electrophysiologically distinct cell populations coexist side-by-side within a single segment, constituting an electrical mosaic.…”

Section: Archer Et Al Ionic Heterogeneity Explains Vascular Diversitymentioning

confidence: 99%

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Preferential Expression and Function of Voltage-Gated, O ₂ -Sensitive K ⁺ Channels in Resistance Pulmonary Arteries Explains Regional Heterogeneity in Hypoxic Pulmonary Vasoconstriction

Archer

Thébaud

et al. 2004

Circulation Research

179

178

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Abstract-Hypoxic pulmonary vasoconstriction (HPV) is initiated by inhibition of O 2 -sensitive, voltage-gated (Kv) channels in pulmonary arterial smooth muscle cells (PASMCs). Kv inhibition depolarizes membrane potential (E M ), thereby activating Ca 2ϩ influx via voltage-gated Ca 2ϩ channels. HPV is weak in extrapulmonary, conduit pulmonary arteries (PA) and strong in precapillary resistance arteries. We hypothesized that regional heterogeneity in HPV reflects a longitudinal gradient in the function/expression of PASMC O 2 -sensitive Kv channels. In adult male Sprague Dawley rats, constrictions to hypoxia, the Kv blocker 4-aminopyridine (4-AP), and correolide, a Kv1.x channel inhibitor, were endothelium-independent and greater in resistance versus conduit PAs. Moreover, HPV was dependent on Kvinhibition, being completely inhibited by pretreatment with 4-AP. Kv1.2, 1.5, Kv2.1, Kv3.1b, Kv4.3, and Kv9.3. mRNA increased as arterial caliber decreased; however, only Kv1.5 protein expression was greater in resistance PAs. Resistance PASMCs had greater K ϩ current (I K ) and a more hyperpolarized E M and were uniquely O 2 Ϫ and correolide-sensitive. The O 2 -sensitive current (active at Ϫ65 mV) was resistant to iberiotoxin, with minimal tityustoxin sensitivity. In resistance PASMCs, 4-AP and hypoxia inhibited I K 57% and 49%, respectively, versus 34% for correolide. Intracellular administration of anti-Kv1.5 antibodies inhibited correolide's effects. The hypoxia-sensitive, correolide-insensitive I K (15%) was conducted by Kv2.1. Anti-Kv1.5 and anti-Kv2.1 caused additive depolarization in resistance PASMCs (Kv1.5ϾKv2.1) and inhibited hypoxic depolarization. Heterologously expressed human PASMC Kv1.5 generated an O 2 Ϫ and correolide-sensitive I K like that in resistance PASMCs. In conclusion, Kv1.5 and Kv2.1 account for virtually all the O 2 -sensitive current. HPV occurs in a Kv-enriched resistance zone because resistance PASMCs preferentially express O 2 -sensitive Kv-channels. Key Words: immunoelectropharmacology Ⅲ laser capture microdissection Ⅲ voltage-gated channels Ⅲ pulmonary circulation Ⅲ adenoviral gene transfer T he adult pulmonary circulation is a low-resistance circuit designed for gas exchange that is perfused by a thinwalled, afterload-intolerant right ventricle. The pulmonary vasculature consists of large, elastic, extraparenchymal "conduit" arteries and small, muscular intrapulmonary arteries, which control regional distribution of blood flow and largely determine pulmonary vascular resistance (PVR). Hypoxic pulmonary vasoconstriction (HPV) is a widely conserved mechanism for ventilation-perfusion matching. 1 With segmental hypoxia (eg, atelectasis), resistance pulmonary arteries (PAs) serving the hypoxic lobes constrict, diverting blood to better-oxygenated segments, thereby optimizing systemic PO 2 , without increasing PVR. 2,3 Microangiography 4 and micropuncture 5 reveal that HPV primarily occurs in resistance PAs (Ͻ200 mol/L diameter, division 4, and distal), with lesser contributions from larger i...

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“…Previous studies have revealed that hypoxia-induced inhibition of voltage-gated K + (KV) channels may contribute to the contraction of pulmonary arterial smooth muscle cells (PASMCs) by increasing the intracellular calcium concentration ([Ca 2+ ] i ). [14][15][16][17][18][19][20] Hypoxia causes a rapid and reversible increase of [Ca 2+ ] i , which can be blocked by inhibitors of voltage-dependent or store-operated Ca 2+ channels. 21 This increase of [Ca 2+ ] i requires Ca 2+ infl ux and contributes to both the contraction and proliferation of PASMCs.…”

Section: Introductionmentioning

confidence: 99%

The augmenter of liver regeneration protects the kidneys after orthotopic liver transplantation possibly by upregulating HIF-1α and O2-sensitive K+ channels

Chen

Luo

et al. 2011

Surg Today

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KV2.1 channels mediate hypoxic inhibition of IKV in native pulmonary arterial smooth muscle cells of the rat

Cited by 29 publications

References 38 publications

Patho-, physiological roles of voltage-dependent K+ channels in pulmonary arterial smooth muscle cells

Patho-, physiological roles of voltage-dependent K+ channels in pulmonary arterial smooth muscle cells

Preferential Expression and Function of Voltage-Gated, O ₂ -Sensitive K ⁺ Channels in Resistance Pulmonary Arteries Explains Regional Heterogeneity in Hypoxic Pulmonary Vasoconstriction

The augmenter of liver regeneration protects the kidneys after orthotopic liver transplantation possibly by upregulating HIF-1α and O2-sensitive K+ channels

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KV2.1 channels mediate hypoxic inhibition of IKV in native pulmonary arterial smooth muscle cells of the rat

Cited by 29 publications

References 38 publications

Patho-, physiological roles of voltage-dependent K+ channels in pulmonary arterial smooth muscle cells

Patho-, physiological roles of voltage-dependent K+ channels in pulmonary arterial smooth muscle cells

Preferential Expression and Function of Voltage-Gated, O 2 -Sensitive K + Channels in Resistance Pulmonary Arteries Explains Regional Heterogeneity in Hypoxic Pulmonary Vasoconstriction

The augmenter of liver regeneration protects the kidneys after orthotopic liver transplantation possibly by upregulating HIF-1α and O2-sensitive K+ channels

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Preferential Expression and Function of Voltage-Gated, O ₂ -Sensitive K ⁺ Channels in Resistance Pulmonary Arteries Explains Regional Heterogeneity in Hypoxic Pulmonary Vasoconstriction