Multiple modalities converge on a common gate to control K<sub>2P</sub>channel function

Bagriantsev, Sviatoslav N.; Peyronnet, Rémi; Clark, Kimberly A.; Honoré, Eric; Minor, Daniel L.

doi:10.1038/emboj.2011.230

Cited by 138 publications

(271 citation statements)

References 75 publications

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“…The mutations seen in this study in the TM4 region of TASK3 (A237T, G236R) might be anticipated to interfere with gating of the channel by altering movement of this TM4 region. This could result in either an interaction with the bundle-crossing region of the channel that is in close proximity to this region or, perhaps more likely, interference with transduction of the regulatory signal from the intracellular regulatory components to the gating region at the selectivity filter via TM4, as seen for TREK1 channels (Bagriantsev et al, 2011(Bagriantsev et al, , 2012.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the TM4 region of K2P channels has been suggested to be crucial in transducing gating signals from the cytoplasmic side of the channel to the selectivity filter gate (Bagriantsev et al, 2011(Bagriantsev et al, , 2012Piechotta et al, 2011), so we determined whether mutations of amino acids in this region interfered with gating and regulation of TASK3 channels.…”

Section: Recovery Of Current In Mutated Task3 Channelsmentioning

confidence: 99%

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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%

Section: Recovery Of Current In Mutated Task3 Channelsmentioning

confidence: 99%

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

et al. 2013

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“…How could such interactions between the first and second external loops be communicated to the internal gate of the channel? An answer is suggested by the location of the charged residues in the second external loop just "above" the fourth transmembrane helix, which has been shown to serve as an intracellular gate in K 2P channels (29)(30)(31), implying an activation rearrangement that propagates through the helix to the intracellular gate.…”

Section: Discussionmentioning

confidence: 99%

Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels

Levitz

Royal

Comoglio

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Twik-related K + channel 1 (TREK1), TREK2, and Twik-related arachidonic-acid stimulated K + channel (TRAAK) form the TREK subfamily of two-pore-domain K + (K 2P ) channels. Despite sharing up to 78% sequence homology and overlapping expression profiles in the nervous system, these channels show major differences in their regulation by physiological stimuli. For instance, TREK1 is inhibited by external acidification, whereas TREK2 is activated. Here, we investigated the ability of the members of the TREK subfamily to assemble to form functional heteromeric channels with novel properties. Using single-molecule pull-down (SiMPull) from HEK cell lysate and subunit counting in the plasma membrane of living cells, we show that TREK1, TREK2, and TRAAK readily coassemble. TREK1 and TREK2 can each heterodimerize with TRAAK, but do so less efficiently than with each other. We functionally characterized the heterodimers and found that all combinations form outwardly rectifying potassium-selective channels but with variable voltage sensitivity and pH regulation. TREK1-TREK2 heterodimers show low levels of activity at physiological external pH but, unlike their corresponding homodimers, are activated by both acidic and alkaline conditions. Modeling based on recent crystal structures, along with mutational analysis, suggests that each subunit within a TREK1-TREK2 channel is regulated independently via titratable His. Finally, TREK1/TRAAK heterodimers differ in function from TRAAK homodimers in two critical ways: they are activated by both intracellular acidification and alkalinization and are regulated by the enzyme phospholipase D2. Thus, heterodimerization provides a means for diversifying functionality through an expansion of the channel types within the K 2P channels.potassium channels | single-molecule fluorescence | leak current | combinatorial diversity | heteromerization

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“…Like many K + channels, including the budding-yeast K 2p (47), TREK-1 apparently uses a dynamic filter, where several gain-of-function mutations are found (48). Its quaternary ammonium (QA)-binding site seems accessible from the inside before channel activation, suggesting a static open inner gate (49), although QAs could reach the site through the fenestration now shown in the atomic structure (32,33) (Fig.…”

Section: The Mechanics Of the Lipid Bilayermentioning

confidence: 99%

Feeling the hidden mechanical forces in lipid bilayer is an original sense

Anishkin

Loukin²,

Teng³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

263

216

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Life's origin entails enclosing a compartment to hoard material, energy, and information. The envelope necessarily comprises amphipaths, such as prebiotic fatty acids, to partition the two aqueous domains. The self-assembled lipid bilayer comes with a set of properties including its strong anisotropic internal forces that are chemically or physically malleable. Added bilayer stretch can alter force vectors on embedded proteins to effect conformational change. The force-from-lipid principle was demonstrated 25 y ago when stretches opened purified Escherichia coli MscL channels reconstituted into artificial bilayers. This reductionistic exercise has rigorously been recapitulated recently with two vertebrate mechanosensitive K + channels (TREK1 and TRAAK). Membrane stretches have also been known to activate various voltage-, ligand-, or Ca 2+ -gated channels. Careful analyses showed that Kv, the canonical voltage-gated channel, is in fact exquisitely sensitive even to very small tension. In an unexpected context, the canonical transient-receptor-potential channels in the Drosophila eye, long presumed to open by ligand binding, is apparently opened by membrane force due to PIP 2 hydrolysis-induced changes in bilayer strain. Being the intimate medium, lipids govern membrane proteins by physics as well as chemistry. This principle should not be a surprise because it parallels water's paramount role in the structure and function of soluble proteins. Today, overt or covert mechanical forces govern cell biological processes and produce sensations. At the genesis, a bilayer's response to osmotic force is likely among the first senses to deal with the capricious primordial sea. mechanosensitivity | force sensing | channel gating | bilayer mechanics | touch

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Multiple modalities converge on a common gate to control K_2Pchannel function

Cited by 138 publications

References 75 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

Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels

Feeling the hidden mechanical forces in lipid bilayer is an original sense

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Multiple modalities converge on a common gate to control K2Pchannel function

Cited by 138 publications

References 75 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

Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels

Feeling the hidden mechanical forces in lipid bilayer is an original sense

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Multiple modalities converge on a common gate to control K_2Pchannel function