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ML277 activates KCNQ1. 27 / 27
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"ML277 and R-L3 are two small-molecule activators of KCNQ1, the pore-forming subunit of the slowly activating potassium channel I Ks ."
35957984
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"ML277 and R-L3 enhance KCNQ1 current amplitude and slow deactivation."
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"ML277 activates KCNQ1 in a sub-micromolar range (Yu, 2010)."
35957984
sparser
"The observation that the ML277-induced opening of KCNQ1 is independent of PIP 2 is supported by a previous electrophysiology study, which showed that ML277 can activate KCNQ1 with the PIP 2 depleted by the Ciona intestinalis voltage sensor-containing phosphatase upon membrane depolarization ( xref )."
36763058
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"ML277 selectively enhances the activities of KCNQ1, but not the closely related KCNQ2."
35957984
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"ML277 preferentially activates Kv7.1 in the absence of the KCNE1 β-subunit and is less effective at potentiating KCNQ1 when saturated with KCNE1 (4:4 ratio)."
37234204
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"The ability of ML277 to abolish calcium transient and action potential alternans in rabbit atrial myocytes (14), and reverse decreased IKs to partially restore action potential duration in LQT1 patient-derived human iPSC-cardiomyocytes (15), has led others to report IKs may have therapeutic value as an antiarrhythmic target.Here, we demonstrate that ML277 can impart cardioprotection in cellular and whole-heart models of acute coronary syndromes, via a mechanism involving action potential shortening and reduced Ca accumulation, similar to established cardioprotective pathways."
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"Of note, ML277 can only activate KCNQ1 but not I with saturated KCNE1 (21, 39)."
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"A study revealed that ML277 and R-L3 enhanced Kv7.1 in homozygote KCNQ1-KCNE1-G52R and KCNQ1-KCNE1-L51H, as well as in channel complexes that imitate heterogeneous expression of Kv7.1 variants found in patients."
38653189
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"Furthermore, we found that a small molecule, ML277, which binds at the center of the phosphorylation axis, rescues the defective cAMP effects of multiple high-risk LQT1 variants."
39166328
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"ML277 Enhances PIP2 Affinity and cAMP Sensitivity of KCNQ1."
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"This activation of KCNQ1 by ML277, which does not affect the CTD and the CaM, is not observed in other structures of the KCNQ family ( xref , xref , xref ), supporting the unique feature of ML277 in enhancing the VSD-PD coupling ( xref )."
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"On the other hand, we found that ML277 was able to enhance the cAMP effects of A341V (A341V+KCNQ1) and V254M (V254M+KCNQ1) under heterozygous conditions (103.8±13.7% and 95.5±5.5% current increase; P=7.0×10 and P=6.3×10 , respectively, Figure 8H and 8J)."
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"Using single-channel recordings, Eldstrom et al. demonstrate that ML277, a relatively specific activator of KCNQ1 channels, enhances KCNQ1 single-channel kinetics."
34636894
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"ML277 increases the amplitude of KCNQ1 whole-cell and single-channel currents."
34636894
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"ML277 increased KCNQ1 tail currents by 8.5 ± 1.8-fold at +60 mV at a concentration of 1 µM (Fig. 1 D; and Fig. S1, C and D)."
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"ML277 specifically enhances the fully activated open state of KCNQ1 by modulating VSD-pore coupling."
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"This group [XREF_BIBR] later found that ML277 potentiates heteromultimeric KCNQ1 and KCNE1 channels but the increasing KCNE1 expression level reduced and eventually abolished ML277 's effect on KCNQ1 and KCNE1 channels, indicating a competition between KCNE1 and ML277 when interacting with KCNQ1."
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"ML277 is a potent activator of KV7.1 ( Yu et al ., 2013 ) with a 100-fold increase in selectivity for KV7.1 compared to KV7.2-5 ( Yu et al ., 2013 ) ."
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"We have systematically investigated the functional effects of ML277 on the KCNQ1 channel expressed in Xenopus oocytes and found that ML277 specifically enhances the AO state VSD-PD coupling of the KCNQ1 channel (6) (Fig. 1B)."
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"All the evidence consistently supports the mechanism that ML277 specifically enhances the AO state VSD-PD coupling of the KCNQ1 channel.The membrane lipid PIP , on the other hand, mediates the VSD-PD coupling processes of both IO and AO states."
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"The observation that the ML277-induced opening of KCNQ1 is independent of PIP is supported by a previous electrophysiology study, which showed that ML277 can activate KCNQ1 with the PIP depleted by the Ciona intestinalis voltage sensor-containing phosphatase upon membrane depolarization (37)."
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"This activation of KCNQ1 by ML277, which does not affect the CTD and the CaM, is not observed in other structures of the KCNQ family (8, 43, 44), supporting the unique feature of ML277 in enhancing the VSD-PD coupling (6)."
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"Structural and electrophysiological basis for the modulation of KCNQ1 channel currents by ML277."
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"Structural insights for the modulation of KCNQ1 channel by ML277."
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"Here, in contrast with the insensitivity of KCNQ1/KCNE1 (WT) and KCNQ1-D76N channels to ML277, we found that ML277 increased KCNQ1/KCNE1-L51H currents, shifted the conductance voltage curve in the negative direction, and slowed deactivation of channel activity (Figure 4)."
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"Like expression with the KCNE1-L51H mutant, ML277 and R-L3 both significantly increased KCNQ1/KCNE1-G52R current amplitude, slowed channel deactivation, and caused a hyperpolarizing shift in channel activation (Figure 5), Note that in the absence of drugs, the expressed channels have reduced current amplitude, but the activation and deactivation kinetics differ from KCNQ1 alone, like altered channel activity reported by Ma, et al. and Bianchi (Bianchi et al., 1999; Ma et al., 2003) (see Supplementary Figure S1)."
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