Metabolic and thermal stimuli control K<sub>2P</sub>2.1 (TREK-1) through modular sensory and gating domains

Bagriantsev, Sviatoslav N.; Clark, Kimberly A.; Minor, Daniel L.

doi:10.1038/emboj.2012.171

Cited by 90 publications

(194 citation statements)

References 74 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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“…More recently, this strategy was applied to the study of TREK-1 potassium channel, which is highly temperature-sensitive like TRPV1 27 . Introducing an unstructured triple-glycine peptide between the M4 segment and the C terminus was found to eliminate high temperature-sensitivity, supporting the idea that the C-terminus of TREK-1 is responsible for sensing temperature change 28 . In these studies, insertion of a short, unstructured peptide was used to perturb coupling between…”

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confidence: 63%

Exploring Functional Roles of TRPV1 Intracellular Domains with Unstructured Peptide-Insertion Screening

Yang

et al. 2017

Biophysical Journal

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TRPV1 is a polymodal nociceptor for diverse physical and chemical stimuli that interact with different parts of the channel protein. Recent cryo-EM studies revealed detailed channel structures, opening the door for mapping structural elements mediating activation by each stimulus. Towards this goal, here we have combined unstructured peptide-insertion screening (UPS) with electrophysiological and fluorescence recordings to explore structural and functional roles of the intracellular regions of TRPV1 in mediating various activation stimuli. We found that most of the tightly packed protein regions did not tolerate structural perturbation by UPS when tested, indicating that structural integrity of the intracellular region is critical. In agreement with previous reports, Ca 2+ -dependent desensitization is strongly dependent on both intracellular N-and C-terminal domains; insertions of an unstructured peptide between these domains and the transmembrane core domain nearly eliminated Ca 2+ -dependent desensitization. In contrast, channel activations by capsaicin, low pH, divalent cations, and even heat are mostly intact in mutant channels containing the same insertions. These observations suggest that the transmembrane core domain of TRPV1, but not the intracellular domains, is responsible for sensing these stimuli.TRPV1 ion channel can be directly activated or modulated by capsaicin 1 , heat 1 , extracellular proton 2 , divalent cations 3 , Na + 4 , peptide toxins from spider 5 , centipede 6 , and scorpion 7 , membrane depolarization 8 , intracellular Ca 2+ 9 , and many other factors 10 . A noticeable feature of TRPV1 polymodal activation emerging from biophysical investigations is the existence of non-overlapping activation pathways [11][12][13] . However, except for capsaicin 14-19 , proton 11,20 , and animal toxins 6,21 , the channel structures that sense activation stimuli are poorly defined. Recent cryo-EM studies revealed that the transmembrane core domain of TRPV1 resembles that of tetrameric cation channels, with six transmembrane helical segments surrounding a centrally located ion permeation pore 22,23 . The partially resolved intracellular N-and C-terminal domains contain special structures such as the ankyrin-like repeat domains and the TRP domain that likely play crucial structural and/or functional roles 10 . Arrangement of intracellular domains has been investigated using fluorescence resonance energy transfer 24 . A major task for TRPV1 study in the post-structure era is to assign functional roles to individual structure domains.The unstructured peptide-insertion screening (UPS) strategy had been used to rapidly and reliably obtain information on structure-function relationships in an ion channel even before detailed protein structures were available. In one effective application, isolating the pore domain of yeast TRPY1 channel from the intracellular Ca 2+ -sensing domain with unstructured peptides demonstrated that the pore domain was mechanosensitive 25 . Similarly, unstructured peptide insertion...

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“…These sensors can be partially disengaged from the gating machinery by weakening the connection between the C terminus and TM4. This is accomplished by introducing a treble glycine or alanine replacement at the end of TM4, mutations that presumably impair the C terminus-TM4-SF coupling (Bagriantsev et al, 2012). The idea for C terminus and SF coupling was already present in the work of Zilberberg et al (2000Zilberberg et al ( , 2001, which showed that C terminus phosphorylation affected C-type inactivation gating in KCNK0 channel.…”

Section: An All-encompassing Role For the Selectivitymentioning

confidence: 99%

“…No evidence for differences in the SF or the pore helices between these putative activation states has been found, however. In the TRAAK study (Lolicato et al, 2014), gain-offunction mutant channel structures that had previously been functionally characterized (Bagriantsev et al, 2012) were used to probe the C terminus-TM4-SF coupling hypothesis of gating. In contrast to what has been described here, the structures revealed a situation in which the down conformation was conductive, and the up conformation corresponded to the closed channel; this discordant finding of Lolicato et al (2014) remains unexplained.…”

Section: A Novel Hypothesis To Explain Traak Mechanosensitivitymentioning

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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Metabolic and thermal stimuli control K_2P2.1 (TREK-1) through modular sensory and gating domains

Cited by 90 publications

References 74 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

Exploring Functional Roles of TRPV1 Intracellular Domains with Unstructured Peptide-Insertion Screening

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

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Metabolic and thermal stimuli control K2P2.1 (TREK-1) through modular sensory and gating domains

Cited by 90 publications

References 74 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

Exploring Functional Roles of TRPV1 Intracellular Domains with Unstructured Peptide-Insertion Screening

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

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Metabolic and thermal stimuli control K_2P2.1 (TREK-1) through modular sensory and gating domains

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