Acid-sensitive TWIK and TASK Two-pore Domain Potassium Channels Change Ion Selectivity and Become Permeable to Sodium in Extracellular Acidification

Ma, Liqun; Zhang, Xuexin; Zhou, Min; Chen, Haijun

doi:10.1074/jbc.m112.398164

Cited by 51 publications

(45 citation statements)

References 43 publications

(58 reference statements)

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“…These are an inactivation (or C-type) gate at the selectivity filter close to the extracellular side of the channel (Cohen et al, 2009) and an activation gate at the bundle-crossing region of the channel Cohen et al, 2009). For TASK3 channels, there is good evidence that regulators, such as extracellular acidification (Kim et al, 2000;Rajan et al, 2000;Ma et al, 2012;González et al, 2013) and extracellular zinc (Clarke et al, 2004(Clarke et al, , 2008González et al, 2013), act at the selectivity filter to gate the channel. It is less clear, however, whether intracellular regulators, such as those arising after activation of Gaq, interact with the bundle-crossing gate or the selectivity filter gate or even whether the bundle-crossing region acts as a true gate of K2P channels.…”

Section: Discussionmentioning

confidence: 99%

Recovery of Current through Mutated TASK3 Potassium Channels Underlying Birk Barel Syndrome

et al. 2013

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TASK3 (TWIK-related acid-sensitive K 1 channel 3) potassium channels are members of the two-pore-domain potassium channel family. They are responsible for background leak potassium currents found in many cell types. TASK3 channels are genetically imprinted, and a mutation in TASK3 (G236R) is responsible for Birk Barel mental retardation dysmorphism syndrome, a maternally transmitted developmental disorder. This syndrome may arise from a neuronal migration defect during development caused by dysfunctional TASK3 channels. Through the use of whole-cell electrophysiologic recordings, we have found that, although G236R mutated TASK3 channels give rise to a functional current, this current is significantly smaller in an outward direction when compared with wild-type (WT) TASK3 channels. In contrast to WT TASK3 channels, the current is inwardly rectifying. Furthermore, the current through mutated channels is differentially sensitive to a number of regulators, such as extracellular acidification, extracellular zinc, and activation of Gaq-coupled muscarinic (M3) receptors, compared with WT TASK3 channels. The reduced outward current through mutated TASK3_G236R channels can be overcome, at least in part, by both a gain-of-function additional mutation of TASK3 channels (A237T) or by application of the nonsteroidal anti-inflammatory drug flufenamic acid (FFA; 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid). FFA produces a significantly greater enhancement of current through mutated channels than through WT TASK3 channels. We propose that pharmacologic enhancement of mutated TASK3 channel current during development may, therefore, provide a potentially useful therapeutic strategy in the treatment of Birk Barel syndrome.

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Section: Discussionmentioning

confidence: 99%

Recovery of Current through Mutated TASK3 Potassium Channels Underlying Birk Barel Syndrome

et al. 2013

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“…[14][15][16][17] We use whole-cell currents of K 2P channels in transfected CHO cells to assess their open rectification with the GHK current equation, based on 2 basic assumptions. First, recorded whole-cell currents are K C -selective currents via K 2P channels.…”

Section: Resultsmentioning

confidence: 99%

“…All tested K 2P cDNAs were cloned in pMAX or pRAT vectors described previously, 14,15 except that TWIK-2 cDNA was cloned into pEYFP-C1 vectors. CHO cells at least 80% confluence were transfected by Lipofectamine 2000 (Invitrogen) with 3 mg of K 2P channel plasmids and 1 mg of pEGFP plasmids and studied 24 hours later.…”

Section: Methodsmentioning

confidence: 99%

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Classification of 2-pore domain potassium channels based on rectification under quasi-physiological ionic conditions

Chen¹,

Zuo²,

Zhang³

et al. 2014

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“…Extracellular acidification turns TWIK-1 channels from K 1 -selective to monovalent cation-permeable channels (Chatelain et al, 2012;Ma et al, 2012). Histidine 122 is the H 1 sensor in TWIK-1, but other unidentified sites also contribute to modulation by acidification.…”

Section: Gating At the Selectivity Filter Of K 2p Channelsmentioning

confidence: 99%

Gating, Regulation, and Structure in K_2P K⁺ Channels: In Varietate Concordia?

et al. 2016

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1 channels with two pore domains in tandem associate as dimers to produce so-called background conductances that are regulated by a variety of stimuli. Whereas gating in K 2P channels has been poorly understood, recent developments have provided important clues regarding the gating mechanism for this family of proteins. Two modes of gating present in other K 1 channels have been considered. The first is the so-called activation gating that occurs by bundle crossing and the splaying apart of pore-lining helices commanding ion passage. The second mode involves a change in conformation at the selectivity filter (SF), which impedes ion flow at this narrow portion of the conduction pathway and accounts for extracellular pH modulation of several K 2P channels. Although some evidence supports the existence of an activation gate in K 2P channels, recent results suggest that perhaps all stimuli, even those sensed at a distant location in the protein, are also mediated by SF gating. Recently resolved crystal structures of K 2P channels in conductive and nonconductive conformations revealed that the nonconductive state is reached by blockade by a lipid acyl chain that gains access to the channel cavity through intramembrane fenestrations. Here we discuss whether this novel type of gating, proposed so far only for membrane tension gating, might mediate gating in response to other stimuli or whether SF gating is the only type of opening/closing mechanism present in K 2P channels.

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Acid-sensitive TWIK and TASK Two-pore Domain Potassium Channels Change Ion Selectivity and Become Permeable to Sodium in Extracellular Acidification

Abstract: Background: Two-pore domain K ϩ channels mediate background K ϩ conductance and regulate cellular function.

Cited by 51 publications

References 43 publications

Recovery of Current through Mutated TASK3 Potassium Channels Underlying Birk Barel Syndrome

Recovery of Current through Mutated TASK3 Potassium Channels Underlying Birk Barel Syndrome

Classification of 2-pore domain potassium channels based on rectification under quasi-physiological ionic conditions

Gating, Regulation, and Structure in K_2P K⁺ Channels: In Varietate Concordia?

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Acid-sensitive TWIK and TASK Two-pore Domain Potassium Channels Change Ion Selectivity and Become Permeable to Sodium in Extracellular Acidification

Abstract: Background: Two-pore domain K ϩ channels mediate background K ϩ conductance and regulate cellular function.

Cited by 51 publications

References 43 publications

Recovery of Current through Mutated TASK3 Potassium Channels Underlying Birk Barel Syndrome

Recovery of Current through Mutated TASK3 Potassium Channels Underlying Birk Barel Syndrome

Classification of 2-pore domain potassium channels based on rectification under quasi-physiological ionic conditions

Gating, Regulation, and Structure in K2P K+ Channels: In Varietate Concordia?

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Gating, Regulation, and Structure in K_2P K⁺ Channels: In Varietate Concordia?