The pore structure and gating mechanism of K2P channels

Piechotta, Paula L; Rapedius, Markus; Stansfeld, Phillip J.; Bollepalli, Murali K.; Ehrlich, G.; Andres-Enguix, Isabelle; Fritzenschaft, Hariolf; Decher, Niels; Sansom, Mark S. P.; Tucker, Stephen J.; Baukrowitz, Thomas

doi:10.1038/emboj.2011.369

Cited by 88 publications

(65 citation statements)

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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. 2B).…”

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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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

View full text Add to dashboard Cite

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“…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%

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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“…By contrast, the gating of K2P channels was thought to occur through their upper gate [56][57][58][59]. However, except for the upper gate, recent evidence shows that K2P channels may also possess a lower bundle-crossing gate, similar to Kv channels [59][60][61]. For TASK3 channels, the pore-lining helices consisting of two highly conserved putative hinge glycines form the lower gate and mutations of these glycines affect channel opening [62].…”

Section: Discussionmentioning

confidence: 99%

Grafting voltage and pharmacological sensitivity in potassium channels

Lan

Fan

et al. 2016

Cell Res

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A classical voltage-gated ion channel consists of four voltage-sensing domains (VSDs). However, the roles of each VSD in the channels remain elusive. We developed a GVTDT (Graft VSD To Dimeric TASK3 channels that lack endogenous VSDs) strategy to produce voltage-gated channels with a reduced number of VSDs. TASK3 channels exhibit a high host tolerance to VSDs of various voltage-gated ion channels without interfering with the intrinsic properties of the TASK3 selectivity filter. The constructed channels, exemplified by the channels grafted with one or two VSDs from Kv7.1 channels, exhibit classical voltage sensitivity, including voltage-dependent opening and closing. Furthermore, the grafted Kv7.1 VSD transfers the potentiation activity of benzbromarone, an activator that acts on the VSDs of the donor channels, to the constructed channels. Our study indicates that one VSD is sufficient to voltage-dependently gate the pore and provides new insight into the roles of VSDs.

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The pore structure and gating mechanism of K2P channels

Cited by 88 publications

References 1 publication

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

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

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

Grafting voltage and pharmacological sensitivity in potassium channels

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