TASK-1 and TASK-3 may form heterodimers in human atrial cardiomyocytes

Rinné, Susanne; Kiper, Aytuğ K.; Schlichthörl, Günter; Dittmann, Sven; Netter, Michael F.; Limberg, Sven H.; Silbernagel, Nicole; Zuzarte, Marylou; Moosdorf, Rainer; Wulf, Hinnerk; Schulze‐Bahr, Eric; Rolfes, Caroline; Decher, Niels

doi:10.1016/j.yjmcc.2015.01.017

Cited by 43 publications

(53 citation statements)

References 32 publications

(84 reference statements)

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“…KCNK9 is thought to be co‐expressed with KCNK3 in various tissues outside of the lung, including in the central nervous system, heart, and adrenal glands, and functional heterodimerization of KCNK3 with KCNK9 in multiple tissues has already been studied 6, 11, 12, 13, 175.…”

Section: Resultsmentioning

confidence: 99%

“…KCNK9, which has been shown to heterodimerize with KCNK3,11 is absent from human lungs of healthy controls and PAH patients (Figure 7A; and see Figure S3D and S3E), but assembles with KCNK3 in tissues where both KCNK9 and KCNK3 are expressed, leading to diversity of channel currents 12, 13, 14. We observed that KCNK9 heterodimerization with WT and G203D KCNK3 increased current activity at physiological pH 7.4 compared with equivalent KCNK3‐only based channels, and suggest that KCNK9 may protect against KCNK3 dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…Adding to the complexity of KCNK3 regulation, the closely related acid‐sensitive KCNK9 channel dimerizes with KCNK3, forming KCNK9‐KCNK3 heterodimeric channels in tissues where both channels are expressed 11, 12, 13, 14, 15. KCNK9 is more maximally activated at pH 7.4 than KCNK3 16, 17.…”

Section: Introductionmentioning

confidence: 99%

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The Impact of Heterozygous KCNK3 Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery

Bohnen

Roman‐Campos

Terrenoire

et al. 2017

JAHA

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BackgroundHeterozygous loss of function mutations in the KCNK3 gene cause hereditary pulmonary arterial hypertension (PAH). KCNK3 encodes an acid‐sensitive potassium channel, which contributes to the resting potential of human pulmonary artery smooth muscle cells. KCNK3 is widely expressed in the body, and dimerizes with other KCNK3 subunits, or the closely related, acid‐sensitive KCNK9 channel.Methods and ResultsWe engineered homomeric and heterodimeric mutant and nonmutant KCNK3 channels associated with PAH. Using whole‐cell patch‐clamp electrophysiology in human pulmonary artery smooth muscle and COS7 cell lines, we determined that homomeric and heterodimeric mutant channels in heterozygous KCNK3 conditions lead to mutation‐specific severity of channel dysfunction. Both wildtype and mutant KCNK3 channels were activated by ONO‐RS‐082 (10 μmol/L), causing cell hyperpolarization. We observed robust gene expression of KCNK3 in healthy and familial PAH patient lungs, but no quantifiable expression of KCNK9, and demonstrated in functional studies that KCNK9 minimizes the impact of select KCNK3 mutations when the 2 channel subunits co‐assemble.ConclusionsHeterozygous KCNK3 mutations in PAH lead to variable loss of channel function via distinct mechanisms. Homomeric and heterodimeric mutant KCNK3 channels represent novel therapeutic substrates in PAH. Pharmacological and pH‐dependent activation of wildtype and mutant KCNK3 channels in pulmonary artery smooth muscle cells leads to membrane hyperpolarization. Co‐assembly of KCNK3 with KCNK9 subunits may provide protection against KCNK3 loss of function in tissues where both KCNK9 and KCNK3 are expressed, contributing to the lung‐specific phenotype observed clinically in patients with PAH because of KCNK3 mutations.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The Impact of Heterozygous KCNK3 Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery

Bohnen

Roman‐Campos

Terrenoire

et al. 2017

JAHA

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“…The SR and cAF versions of the Grandi et al 36 computational model of the human atrial cardiomyocyte, including our recent update with Na + -dependent regulation of I K1 and I K,ACh , 37 was extended with a formulation for the K 2P 3.1 current (Supplemental Methods, Table II, and Figure I in the online-only Data Supplement).…”

Section: Computational Modelingmentioning

confidence: 99%

“…The Grandi et al 36 computational model of the human atrial cardiomyocyte was extended with a formulation for the K 2P 3.1 current based on the experimentally measured I-V relationship ( Figure I in the online-only Data Supplement). The SR and cAF versions of the model were adjusted to reproduce the experimental APD 50 and APD 90 under simulated conditions corresponding to the experimentally used pipette and bath solutions ( Figure 6A and 6B).…”

Section: Computational Analysis Of the Effect Of K 2p 31 Current On mentioning

confidence: 99%

Upregulation of K _2P 3.1 K ⁺ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation

et al. 2015

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Background-Antiarrhythmic management of atrial fibrillation (AF) remains a major clinical challenge. Mechanismbased approaches to AF therapy are sought to increase effectiveness and to provide individualized patient care. K 2P 3.1 (TASK-1 [tandem of P domains in a weak inward-rectifying K + channel-related acid-sensitive K + channel-1]) 2-poredomain K + (K 2P ) channels have been implicated in action potential regulation in animal models. However, their role in the pathophysiology and treatment of paroxysmal and chronic patients with AF is unknown. Methods and Results-Right and left atrial tissue was obtained from patients with paroxysmal or chronic AF and from control subjects in sinus rhythm. Ion channel expression was analyzed by quantitative real-time polymerase chain reaction and Western blot. Membrane currents and action potentials were recorded using voltage-and current-clamp techniques. K 2P 3.1 subunits exhibited predominantly atrial expression, and atrial K 2P 3.1 transcript levels were highest among functional K 2P channels. K 2P 3.1 mRNA and protein levels were increased in chronic AF. Enhancement of corresponding currents in the right atrium resulted in shortened action potential duration at 90% of repolarization (APD 90 ) compared with patients in sinus rhythm. In contrast, K 2P 3.1 expression was not significantly affected in subjects with paroxysmal AF. Pharmacological K 2P 3.1 inhibition prolonged APD 90 in atrial myocytes from patients with chronic AF to values observed among control subjects in sinus rhythm. Conclusions-Enhancement of atrium-selective K 2P 3.1 currents contributes to APD shortening in patients with chronic AF, and K 2P 3.1 channel inhibition reverses AF-related APD shortening. These results highlight the potential of K 2P 3.1 as a novel drug target for mechanism-based AF therapy.

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Potassium Channels in the Heart

Thomsen

2018

Channelopathies in Heart Disease

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TASK-1 and TASK-3 may form heterodimers in human atrial cardiomyocytes

Cited by 43 publications

References 32 publications

The Impact of Heterozygous KCNK3 Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery

The Impact of Heterozygous KCNK3 Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery

Upregulation of K _2P 3.1 K ⁺ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation

Potassium Channels in the Heart

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TASK-1 and TASK-3 may form heterodimers in human atrial cardiomyocytes

Cited by 43 publications

References 32 publications

The Impact of Heterozygous KCNK3 Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery

The Impact of Heterozygous KCNK3 Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery

Upregulation of K 2P 3.1 K + Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation

Potassium Channels in the Heart

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Upregulation of K _2P 3.1 K ⁺ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation