TASK-1 (KCNK3) channels in the lung: from cell biology to clinical implications

Olschewski, Andrea; Veale, Emma L.; Nagy, Bence; Nagaraj, Chandran; Kwapiszewska, Grażyna; Antigny, Fabrice; Lambert, Mélanie; Humbert, Marc; Czirják, Gábor; Enyedi, Péter; Mathie, Alistair

doi:10.1183/13993003.00754-2017

Cited by 67 publications

(57 citation statements)

References 125 publications

(153 reference statements)

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“…) because, without the latter, enhancement of a current with reduced K selectivity would exacerbate any pathophysiological responses resulting from cellular depolarization, as would be the case for PASMCs in PAH (Olschewski et al . ). However, neither of the two mutant channels in the present study showed any recovery of current following exposure to either alkaline pH or ONO‐RS‐082.…”

Section: Discussionmentioning

confidence: 97%

“…The non‐inactivating K current in rat, rabbit and human PASMCs has functional characteristics of TASK‐1 channels (Olschewski et al . ), although this may not be the case in mouse PASMCs (Manoury et al . , ).…”

Section: Discussionmentioning

confidence: 99%

“…, Hemnes & Humbert , Olschewski et al . ). Down‐regulation, inhibition and mutations of these channels resulting in loss of channel function have been shown to contribute to cell proliferation, resistance to apoptosis and vasoconstriction in pulmonary arterial smooth muscle cells (PASMCs) (Remillard et al .…”

Section: Introductionmentioning

confidence: 97%

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Characterization and regulation of wild‐type and mutant TASK‐1 two pore domain potassium channels indicated in pulmonary arterial hypertension

Cunningham

Holden

Escribano

et al. 2018

The Journal of Physiology

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Key points The TASK‐1 channel gene (KCNK3) has been identified as a possible disease‐causing gene in heritable pulmonary arterial hypertension (PAH). In the present study, we show that novel mutated TASK‐1 channels, seen in PAH patients, have a substantially reduced current compared to wild‐type TASK‐1 channels. These mutated TASK‐1 channels are located at the plasma membrane to the same degree as wild‐type TASK‐1 channels. ONO‐RS‐082 and alkaline pH 8.4 both activate TASK‐1 channels but do not recover current through mutant TASK‐1 channels. We show that the guanylate cyclase activator, riociguat, a novel treatment for PAH, enhances current through TASK‐1 channels but does not recover current through mutant TASK‐1 channels. Abstract Pulmonary arterial hypertension (PAH) affects ∼15–50 people per million. KCNK3, the gene that encodes the two pore domain potassium channel TASK‐1 (K2P3.1), has been identified as a possible disease‐causing gene in heritable PAH. Recently, two new mutations have been identified in KCNK3 in PAH patients: G106R and L214R. The present study aimed to characterize the functional properties and regulation of wild‐type (WT) and mutated TASK‐1 channels and determine how these might contribute to PAH and its treatment. Currents through WT and mutated human TASK‐1 channels transiently expressed in tsA201 cells were measured using whole‐cell patch clamp electrophysiology. Localization of fluorescence‐tagged channels was visualized using confocal microscopy and quantified with in‐cell and on‐cell westerns. G106R or L214R mutated channels were located at the plasma membrane to the same degree as WT channels; however, their current was markedly reduced compared to WT TASK‐1 channels. Functional current through these mutated channels could not be restored using activators of WT TASK‐1 channels (pH 8.4, ONO‐RS‐082). The guanylate cyclase activator, riociguat, enhanced current through WT TASK‐1 channels; however, similar to the other activators investigated, riociguat did not have any effect on current through mutated TASK‐1 channels. Thus, novel mutations in TASK‐1 seen in PAH substantially alter the functional properties of these channels. Current through these channels could not be restored by activators of TASK‐1 channels. Riociguat enhancement of current through TASK‐1 channels could contribute to its therapeutic benefit in the treatment of PAH.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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Characterization and regulation of wild‐type and mutant TASK‐1 two pore domain potassium channels indicated in pulmonary arterial hypertension

Cunningham

Holden

Escribano

et al. 2018

The Journal of Physiology

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“…The mechanism behind the partial depolarization remains to be identified. A plethora of additional oxygen-sensitive components in PASMC have been suggested (1), including hypoxia-sensitive potassium channels (34,35). Substituting…”

Section: Discussionmentioning

confidence: 99%

Bypassing mitochondrial complex III using alternative oxidase inhibits acute pulmonary oxygen sensing

et al. 2020

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Mitochondria play an important role in sensing both acute and chronic hypoxia in the pulmonary vasculature, but their primary oxygen-sensing mechanism and contribution to stabilization of the hypoxia-inducible factor (HIF) remains elusive. Alteration of the mitochondrial electron flux and increased superoxide release from complex III has been proposed as an essential trigger for hypoxic pulmonary vasoconstriction (HPV). We used mice expressing a tunicate alternative oxidase, AOX, which maintains electron flux when respiratory complexes III and/or IV are inhibited. Respiratory restoration by AOX prevented acute HPV and hypoxic responses of pulmonary arterial smooth muscle cells (PASMC), acute hypoxia-induced redox changes of NADH and cytochrome c, and superoxide production. In contrast, AOX did not affect the development of chronic hypoxia-induced pulmonary hypertension and HIF-1α stabilization. These results indicate that distal inhibition of the mitochondrial electron transport chain in PASMC is an essential initial step for acute but not chronic oxygen sensing.

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“…K 2P are very weakly sensitive or insensitive to the classical K + channel blockers, such as TEA, Ba +2 , Cs + , and 4‐AP. These channels are sensitive to pH and are inhibited by acidification of the extracellular fluid .…”

Section: Basic Properties Of Potassium Channelsmentioning

confidence: 99%

Potassium channels in vascular smooth muscle: a pathophysiological and pharmacological perspective

Doğan

Yıldız

Arslan

et al. 2019

Fundamemntal Clinical Pharma

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Potassium (K+) ion channel activity is an important determinant of vascular tone by regulating cell membrane potential (MP). Activation of K+ channels leads to membrane hyperpolarization and subsequently vasodilatation, while inhibition of the channels causes membrane depolarization and then vasoconstriction. So far five distinct types of K+ channels have been identified in vascular smooth muscle cells (VSMCs): Ca+2‐activated K+ channels (BKCa), voltage‐dependent K+ channels (KV), ATP‐sensitive K+ channels (KATP), inward rectifier K+ channels (Kir), and tandem two‐pore K+ channels (K2P). The activity and expression of vascular K+ channels are changed during major vascular diseases such as hypertension, pulmonary hypertension, hypercholesterolemia, atherosclerosis, and diabetes mellitus. The defective function of K+ channels is commonly associated with impaired vascular responses and is likely to become as a result of changes in K+ channels during vascular diseases. Increased K+ channel function and expression may also help to compensate for increased abnormal vascular tone. There are many pharmacological and genotypic studies which were carried out on the subtypes of K+ channels expressed in variable amounts in different vascular beds. Modulation of K+ channel activity by molecular approaches and selective drug development may be a novel treatment modality for vascular dysfunction in the future. This review presents the basic properties, physiological functions, pathophysiological, and pharmacological roles of the five major classes of K+ channels that have been determined in VSMCs.

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TASK-1 (KCNK3) channels in the lung: from cell biology to clinical implications

Cited by 67 publications

References 125 publications

Characterization and regulation of wild‐type and mutant TASK‐1 two pore domain potassium channels indicated in pulmonary arterial hypertension

Characterization and regulation of wild‐type and mutant TASK‐1 two pore domain potassium channels indicated in pulmonary arterial hypertension

Bypassing mitochondrial complex III using alternative oxidase inhibits acute pulmonary oxygen sensing

Potassium channels in vascular smooth muscle: a pathophysiological and pharmacological perspective

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