A Specific Two-pore Domain Potassium Channel Blocker Defines the Structure of the TASK-1 Open Pore

Streit, Anne K.; Netter, Michael F.; Kempf, Franca; Walecki, Magdalena; Rinné, Susanne; Bollepalli, Murali K.; Preisig‐Müller, Regina; Renigunta, Vijay; Daut, Jürgen; Baukrowitz, Thomas; Sansom, Mark S. P.; Stansfeld, Phillip J.; Decher, Niels

doi:10.1074/jbc.m111.227884

Cited by 75 publications

(171 citation statements)

References 29 publications

(36 reference statements)

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“…The compound inhibited K 2P 3.1 as an open-channel blocker with an IC 50 ϭ 7 nM in CHO cells, and bound to the closely related K 2P 9.1 with a 10-fold lower affinity. Furthermore, A1899 did not affect a large panel of other channels expressed in human cardiomyocytes (407). The recent publication of the human K 2P 1.1 crystal structure could enable the development of specific drugs (257).…”

Section: Cardiac Potassium Channels and Arrhythmiamentioning

confidence: 99%

“…Furthermore, the channels were highly sensitive to changes in external pH near physiological values (109) and were inhibited by the endocannabinoid anandamide (270). Meanwhile, more selective tool compounds have been developed (356,407). The aromatic carbonamide A293 (Sanofi-Aventis) was shown to inhibit K 2P 3.1 currents at low concentrations (IC 50 222 Ϯ 38 nM in Xenopus laevis oocytes).…”

Section: Two-pore Domain K ϩ Channelsmentioning

confidence: 99%

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Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

Schmitt

Grunnet

Olesen

2014

Physiological Reviews

186

192

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About 10 distinct potassium channels in the heart are involved in shaping the action potential. Some of the K+ channels are primarily responsible for early repolarization, whereas others drive late repolarization and still others are open throughout the cardiac cycle. Three main K+ channels drive the late repolarization of the ventricle with some redundancy, and in atria this repolarization reserve is supplemented by the fairly atrial-specific KV1.5, Kir3, KCa, and K2P channels. The role of the latter two subtypes in atria is currently being clarified, and several findings indicate that they could constitute targets for new pharmacological treatment of atrial fibrillation. The interplay between the different K+ channel subtypes in both atria and ventricle is dynamic, and a significant up- and downregulation occurs in disease states such as atrial fibrillation or heart failure. The underlying posttranscriptional and posttranslational remodeling of the individual K+ channels changes their activity and significance relative to each other, and they must be viewed together to understand their role in keeping a stable heart rhythm, also under menacing conditions like attacks of reentry arrhythmia.

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Section: Cardiac Potassium Channels and Arrhythmiamentioning

confidence: 99%

Section: Two-pore Domain K ϩ Channelsmentioning

confidence: 99%

Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

Schmitt

Grunnet

Olesen

2014

Physiological Reviews

186

192

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“…Mutagenesis and modeling studies of TASK-1 by Streit et al (2011) and Kiper et al (2015) using A1899 and other inhibitory compounds have suggested an intracellular potassium channel pore site of action. We undertook homology modeling, docking, and scanning aspartate mutagenesis studies to determine where on the TASK-3 channel the breathing stimulant compounds PKTHPP, A1899, and doxapram act.…”

Section: Breathing Stimulants Block the Task-3 Potassium Channel Porementioning

confidence: 99%

“…A number of selective, high-potency TASK-blocking compounds have been identified, and some are in clinical use or have undergone preclinical studies (Putzke et al, 2007;Brendel et al, 2009;Streit et al, 2011;Coburn et al, 2012;Flaherty et al, 2014). Doxapram is a breathing stimulant and carotid body-activating drug developed in the 1960s for use in human and veterinary medicine (Lunsford et al, 1964).…”

Section: Introductionmentioning

confidence: 99%

Breathing Stimulant Compounds Inhibit TASK-3 Potassium Channel Function Likely by Binding at a Common Site in the Channel Pore

et al. 2015

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Compounds PKTHPP (1-{1-[6-(biphenyl-4-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidin-4-yl]piperidin-4-yl}propan-1-one), A1899 (2ʹ9-[(4-methoxybenzoylamino)methyl]biphenyl-2-carboxylic acid 2,4-difluorobenzylamide), and doxapram inhibit TASK-1 (KCNK3) and TASK-3 (KCNK9) tandem pore (K 2P ) potassium channel function and stimulate breathing. To better understand the molecular mechanism(s) of action of these drugs, we undertook studies to identify amino acid residues in the TASK-3 protein that mediate this inhibition. Guided by homology modeling and molecular docking, we hypothesized that PKTHPP and A1899 bind in the TASK-3 intracellular pore. To test our hypothesis, we mutated each residue in or near the predicted PKTHPP and A1899 binding site (residues 118-128 and 228-248), individually, to a negatively charged aspartate. We quantified each mutation's effect on TASK-3 potassium channel concentration response to PKTHPP. Studies were conducted on TASK-3 transiently expressed in Fischer rat thyroid epithelial monolayers; channel function was measured in an Ussing chamber. TASK-3 pore mutations at residues 122 (L122D, E, or K) and 236 (G236D) caused the IC 50 of PKTHPP to increase more than 1000-fold. TASK-3 mutants L122D, G236D, L239D, and V242D were resistant to block by PKTHPP, A1899, and doxapram. Our data are consistent with a model in which breathing stimulant compounds PKTHPP, A1899, and doxapram inhibit TASK-3 function by binding at a common site within the channel intracellular pore region, although binding outside the channel pore cannot yet be excluded.

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“…24 Four of the mutations fall in the pore domains in KCNK3 that are critical for the pH sensitivity and potassium selectivity of this potassiumchannel family. 25,26 Two of the mutations, G97R and G203D, are in the pore-domain GXG triplet selectivity filters (in which X is any amino acid) of KCNK3 ( Fig. 2A) and may have their deleterious effects as a result of alterations in potassium selectivity.…”

Section: Discussionmentioning

confidence: 99%