Loss of KCNK3 is a hallmark of RV hypertrophy/dysfunction associated with pulmonary hypertension

Lambert, Mélanie; Boët, Angèle; Rücker‐Martin, Catherine; Mendes-Ferreira, Pedro; Capuano, Véronique; Hatem, Stéphane; Adão, Rui; Brás-Silva, Carmen; Hautefort, Aurélie; Michel, Jean Baptiste; Dorfmüller, Peter; Fadel, Élie; Kotsimbos, Tom; Price, Laura; Jourdon, Philippe; Montani, David; Humbert, Marc; Perros, Frédèric; Antigny, Fabrice

doi:10.1093/cvr/cvy016

Cited by 56 publications

(47 citation statements)

References 43 publications

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“…) and a loss of TASK‐1 channel function and expression is a characteristic of right ventricular hypertrophy associated with pulmonary hypertension (Lambert et al . ). Guanylate cyclase activators, endothelin receptor antagonists and prostacyclin analogues are established vascular therapeutic strategies in the treatment of PAH, acting to reduce vasoconstriction and smooth muscle proliferation, and all three will stimulate activation of TASK‐1 channels in PASMCs, which would contribute to their therapeutic benefit.…”

Section: Discussionmentioning

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%

“…Furthermore, a reduction in TASK‐1 channel function has been observed in right ventricular cardiomyoctes prior to the development of right ventricular hypertrophy related to pulmonary hypertension (Lambert et al . ).…”

Section: Introductionmentioning

confidence: 97%

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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“…Lambert et al. reported that KCNK3 function is severely decreased in right ventricle cardiomyocytes during the development of right ventricle hypertrophy in rat models of pulmonary hypertension. Ten different KCNK3 mutations, which cause damaged channel activity, described in PA hypertension so far, and novel candidate drugs to restore KCNK3 function should be investigated .…”

Section: Pathophysiological Roles 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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“…There are fifteen K2P subtypes comprising six subfamilies in which the channel monomers assemble into dimers wherein each subunit contributes two conserved pore forming domains to make the channel pore (Brohawn et al, 2012;Dong et al, 2015;Feliciangeli et al, 2014;Lolicato et al, 2017;Miller and Long, 2012;Rödström et al, 2019). A range of physical and chemical signals control K2P function (Enyedi and Czirjak, 2010;Feliciangeli et al, 2014;Renigunta et al, 2015) and various K2P subtypes have emerging roles in a multitude of physiological responses and pathological conditions such as action potential propagation in myelinated axons (Brohawn et al, 2019;Kanda et al, 2019), anesthetic responses (Heurteaux et al, 2004;Lazarenko et al, 2010), microglial surveillance (Madry et al, 2018), sleep duration (Yoshida et al, 2018), pain (Alloui et al, 2006;Devilliers et al, 2013;Vivier et al, 2017), arrythmia (Decher et al, 2017), ischemia (Heurteaux et al, 2004;Laigle et al, 2012;Wu et al, 2013), cardiac fibrosis (Abraham et al, 2018), depression (Heurteaux et al, 2006), migraine (Royal et al, 2019), intraocular pressure regulation (Yarishkin et al, 2018), and pulmonary hypertension (Lambert et al, 2018). Although there have been recent advances in identifying new K2P modulators (Bagriantsev et al, 2013;Lolicato et al, 2017;Pope et al, 2018;Su et al, 2016;Tian et al, 2019;Vivier et al, 2017;Wright et al, 2019) and in defining key structural aspects of K2P channel pharmacolog...…”

Section: Introductionmentioning

confidence: 99%

Polynuclear ruthenium amines inhibit K_2P channels via a ‘finger in the dam’ mechanism

Pope¹,

Lolicato²,

Minor³

2019

Preprint

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The trinuclear ruthenium amine Ruthenium Red (RuR) inhibits diverse ion channels including K2P potassium channels, TRPs, the mitochondrial calcium uniporter, CALHMs, ryanodine receptors, and Piezos. Despite this extraordinary array, there is very limited information for how RuR engages its targets. Here, using X-ray crystallographic and electrophysiological studies of an RuR-sensitive K2P, K2P2.1 (TREK-1) I110D, we show that RuR acts by binding an acidic residue pair comprising the 'Keystone inhibitor site' under the K2P CAP domain archway above the channel pore. We further establish that Ru360, a dinuclear ruthenium amine not known to affect K2Ps, inhibits RuR-sensitive K2Ps using the same mechanism. Structural knowledge enabled a generalizable RuR 'super-responder' design strategy for creating K2Ps having nanomolar sensitivity. Together, the data define a 'finger in the dam' inhibition mechanism acting at a novel K2P inhibitor binding site.These findings highlight the polysite nature of K2P pharmacology and provide a new framework for K2P inhibitor development.

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Loss of KCNK3 is a hallmark of RV hypertrophy/dysfunction associated with pulmonary hypertension

Abstract: Our data indicate that loss of KCNK3 function and expression is a hallmark of the RV hypertrophy/dysfunction associated with PH.

Cited by 56 publications

References 43 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

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

Polynuclear ruthenium amines inhibit K_2P channels via a ‘finger in the dam’ mechanism

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Loss of KCNK3 is a hallmark of RV hypertrophy/dysfunction associated with pulmonary hypertension

Abstract: Our data indicate that loss of KCNK3 function and expression is a hallmark of the RV hypertrophy/dysfunction associated with PH.

Cited by 56 publications

References 43 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

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

Polynuclear ruthenium amines inhibit K2P channels via a ‘finger in the dam’ mechanism

Contact Info

Product

Resources

About

Polynuclear ruthenium amines inhibit K_2P channels via a ‘finger in the dam’ mechanism