The selectivity, voltage-dependence and acid sensitivity of the tandem pore potassium channel TASK-1: contributions of the pore domains

Yuill, Kathryn H.; Stansfeld, Phillip J.; Ashmole, Ian; Sutcliffe, Michael J.; Stanfield, Peter

doi:10.1007/s00424-007-0282-7

Cited by 31 publications

(42 citation statements)

References 55 publications

(126 reference statements)

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“…alters the selectivity filter arrangement, thereby increasing sodium permeability (32)(33)(34). Lowering the pH of a 100-mM sodium solution from 9.0 to 7.0 caused a significant right shift of 20 mV (Ϫ134.4 Ϯ 0.6 to Ϫ114.3 Ϯ 0.9, mean Ϯ S.E., n ϭ 17) in the measured reversal potential of oocytes expressing wild type (WT) K 2P 2.1 channels (Fig.…”

Section: Resultsmentioning

confidence: 98%

A Novel Mechanism for Human K2P2.1 Channel Gating

Golan‐Cohen

Ben-Abu

Hen

et al. 2008

Journal of Biological Chemistry

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The mammalian K 2P 2.1 potassium channel (TREK-1, KCNK2) is highly expressed in excitable tissues, where it plays a key role in the cellular mechanisms of neuroprotection, anesthesia, pain perception, and depression. Here, we report that external acidification, within the physiological range, strongly inhibits the human K 2P 2.1 channel by inducing "C-type" closure. We have identified two histidine residues (i.e. His-87 and His-141), located in the first external loop of the channel, that govern the response of the channel to external pH. We demonstrate that these residues are within physical proximity to glutamate 84, homologous to Shaker Glu-418, KcsA Glu-51, and KCNK0 Glu-28 residues, all previously argued to stabilize the outer pore gate in the open conformation by forming hydrogen bonds with poreadjacent residues. We thus propose a novel mechanism for pH sensing in which protonation of His-141 and His-87 generates a local positive charge that serves to draw Glu-84 away from its natural interactions, facilitating the collapse of the selectivity filter region. In accordance with this proposed mechanism, low pH modified K 2P 2.1 selectivity toward potassium. Moreover, the proton-mediated effect was inhibited by external potassium ions and was enhanced by a mutation (S164Y) known to accelerate C-type gating. Furthermore, proton-induced current inhibition was more pronounced at negative potentials. Thus, voltage-dependent C-type gating acceleration by protons represents a novel mechanism for K 2P 2.1 outward rectification.

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Section: Resultsmentioning

confidence: 98%

A Novel Mechanism for Human K2P2.1 Channel Gating

Golan‐Cohen

Ben-Abu

Hen

et al. 2008

Journal of Biological Chemistry

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“…G203D KCNK3 disrupts the conserved “GxG” potassium selectivity filter amino acid sequence in 1 of the channel's 2 pore‐loop domains, a region sensitive to dominant‐negative mutations 24, 25, 26. We first engineered and studied the WT‐G203D KCNK3 heterodimer (Figure 7B, left), and indeed observed severe dominant‐negative dysfunction, as the mutant channels produced small currents across pH 6.4 through 10.4 (Figure 7B and 7C; also see Figure S4).…”

Section: Resultsmentioning

confidence: 99%

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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“…K ϩ dependence of TASK-1 pH o gating is in accord with this concept (11,35). Yuill et al (36) modeled TASK-1 based on the structure of the KcsA channel and first suggested that His-98 sensor was located behind the selectivity filter where its protonation might alter the shape of the SF producing a nonconducting state. The same authors show that site-directed mutagenesis affecting ion selectivity produced concomitant changes in pH o dependence, consistent with SF gating.…”

Section: Discussionmentioning

confidence: 99%