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ML335 activates KCNK2. 21 / 21
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"ML335 and ML402 are remarkably selective, activating K 2.1 (TREK-1) and K 10.1 (TREK-2) but not K 4.1 (TRAAK) [11] (Fig. 4.3)."
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"Because K modulator pocket contains architectural elements that support the selectivity and GOF mutant sites that activate the C-type gate , we asked whether P1/M4 interface structural changes caused by ML335, ML402, or GOF mutation impact C-type gate function.Measurement of K 2.1(TREK-1) in inside-out patches under conditions that potentiate flux-dependent C-type gate activation (150 mM K versus 150 mM Rb ) showed the expected outward rectification (Fig. 4g and k)."
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"Previous studies showed that ML335 strongly activates K 2.1(TREK-1) and K 10.1(TREK-2), but not the third TREK subfamily member K 4.1(TRAAK) unless this channel bears a Q258K mutation creating a cation-π interaction with the modulator upper ring ."
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"This model is also consistent with recent observations that covalent attachment of ML335 derivatives within the K2P modulator site via a conserved serine on PH1 can irreversibly activate TREK channels ."
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"This pocket has been reported to serve as a detector for multiple physiological stimuli and regulates the C-type gates in other K2P channels; for example, it is involved in the activation of TREK1 and TREK2 by ML335, a K2P channel opener (22, 34), proton-induced inhibition of TASK2 and TALK2 (20, 28), and membrane-tension-sensing of TRAAK (14)."
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"Supplementary Figure S2 shows that ML335 significantly activated TREK-1 compared to the vehicle in TREK-1-expressing cells."
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"KKT inhibited the ML335-induced TREK-1 activity in a dose-dependent manner (Figure 1A,B)."
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"Specifically, KKT > 100 µg/mL significantly reduced ML335-induced TREK-1 activation (Figure 1B)."
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"Figure 2 illustrates that Poria significantly suppressed ML335-induced TREK-1 activation."
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"Additionally, five other ingredients, Longan arillus, Bupleuri radix, Ziziphi semen, Zingiberis rhizoma, and Angelicae acutilobae radix, significantly inhibited ML335-induced TREK-1 activation (Figure 2)."
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"In contrast, Glycyrrhizae radix, Saussureae radix, Ginseng radix, Polygalae radix, Astragali radix, Gardeniae fructus, Atractylodis lanceae rhizoma, and Ziziphi fructus failed to activate ML335-induced TREK-1 activities (Figure 2)."
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"Subsequently, we assessed the dose-dependent effects of the six identified active components on ML335-induced TREK-1 activation."
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"Poria, Zingiberis rhizoma, and Angelicae acutilobae radix suppressed ML335-induced TREK-1 activation in a dose-dependent manner (Figure 3A,E,F)."
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"These results indicated that a minimum of 3 µg/mL of the six identified components was required to significantly suppress ML335-induced TREK-1 activity."
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"Among the Poria components (pachymic acid, ergosterol, and adenosine), pachymic acid and adenosine significantly suppressed ML335-induced TREK-1 activation (Figure 4A)."
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"Among the Longan arillus components (myristic acid, myristicin, tartaric acid, corilagin, and gallic acid), myristic acid, myristicin, and gallic acid significantly inhibited ML335-induced TREK-1 activation (Figure 4B)."
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"Among the Bupleuri radix components (saikogenin A, saikosaponin b2, saikogenin D, saikosaponin C, and α-spinasterol), saikogenin A and saikogenin D significantly suppressed ML335-induced TREK-1 activation (Figure 4C)."
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"Among the Ziziphi semen components (betulin, spinosine, magnoflorine, puerarin, swertisin, jujuboside A, jujuboside B, and betulinic acid), magnoflorine, puerarin, and swertisin significantly inhibited ML335-induced TREK-1 activation (Figure 4D)."
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"Among the Zingiberis rhizoma components (6-gingerol, 8-gingerol, 10-gingerol, 6-shogaol, 8-shogaol, 10-shogaol, zingerone, citral, paradol, and borneol), seven components (6-gingerol, 8-gingerol, 6-shogaol, 10-shogaol, citral, paradol, and borneol) significantly reduced ML335-induced TREK-1 activity (Figure 4E)."
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"Among the Angelicae acutilobae radix components (palmitic acid, linoleic acid, nicotinic acid, senkyunolide, senkyunolide H, levistolide A, bergapten, umbelliferone, feruloyltyramine, and xanthotoxin), five components (linoleic acid, senkyunolide H, levistolide A, bergapten, and xanthotoxin) significantly inhibited ML335-induced TREK-1 activity (Figure 4F)."
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"We then started a three-day intra-tracheal treatment course with the novel TREK-1 activating compounds BL1249 or ML335."
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