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Imipramine inhibits KCNH1. 25 / 27
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"First, Eag1 blockers imipramine and astemizole were shown to reduce tumor cell growth."
27698831
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"It was observed that all three doses of imipramine significantly reduced Eag1 currents and conductivity compared with the control."
34729805
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"Thus, we wondered whether two drugs that are widely used to inhibit Eag1, namely, astemizole and imipramine, might affect the cell proliferation of primary retinoblastoma cultures."
31973216
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"The Eag blocker imipramine at 50 muM significantly inhibited the proliferation of SK-OV-3 cell lines at 72 hours of culture (P < 0.001; Figure XREF_FIG) while clofilium (100-3300 nM) did not show any effect on proliferation at any of the time points tested."
21392380
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"Unfortunately, all known hEag1 blockers (including imipramine and astemizole, [6–8] ) also inhibit HERG, which represents a serious difficulty for dissecting the functions of hEag1 and from a practica[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
16949586
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"HEag1 inhibition by the antihistamine astemizole, the tricyclic antidepressant imipramine or hEag1 specific monoclonal antibodies reduces tumor cell proliferation in vitro and in vivo [XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR]."
20105281
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"Both Eag blockers imipramine 50 muM and clofilum 3300 etaM demonstrated no effect on the G0/G1, S or G2M phases of the cell cycle."
21392380
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"We then used electrophysiology and site-directed mutagenesis, guided by molecular dynamics (MD) simulations, to further examine the molecular mechanism of EAG1 current inhibition by imipramine.We found that deletion of the PAS domain substantially decreased EAG1 current inhibition by imipramine, suggesting that the effect of imipramine is, at least in part, mediated via binding to the PAS domain."
37898402
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"Consistent with this, substitution of Tyr71 with glycine and valine increased EAG1 current inhibition by imipramine, while substitution with phenylalanine had no effect on the current inhibition by imipramine."
37898402
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"To investigate the contribution of these residues to the imipramine inhibition of EAG1 currents, they were substituted one by one for glycine, and currents from the mutant channels were recorded over the range of imipramine concentrations (Fig. 4, B–H)."
37898402
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"Importantly, Y71G that increased EAG1 current inhibition by imipramine and D39G/R84G double mutation that decreased EAG1 current inhibition had no effect on V (Fig. 5, O and P)."
37898402
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"In this study, we showed that imipramine inhibits EAG1 channels through binding to their PAS domains and identified specific PAS domain residues that facilitate or limit EAG1 current inhibition by imipramine."
37898402
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"In contrast, the hydrophobic profile of the cavity, and residues D39 and R84 flanking the entrance to the cavity facilitated EAG1 current inhibition by imipramine."
37898402
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"In agreement with this, the substitution of Y71 with structurally similar phenylalanine did not affect EAG1 current inhibition by imipramine, while the substitution of Y71 with a smaller glycine or valine increased EAG1 current inhibition by imipramine."
37898402
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"Consistent with this, substitutions of D39 and R84 residues with glycine substantially decreased EAG current inhibition by imipramine.The residual inhibition of EAG1 channels lacking the PAS domain, combined with the previously reported inhibition of EAG1 channels by imipramine via an open-pore block (27), indicates that imipramine inhibits EAG1 currents by a dual mechanism: by binding to the PAS domain and by blocking the conduction pore."
37898402
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"Imipramine inhibited EAG1 currents in a concentration-dependent manner with the IC of 58.1 ± 9.7 μM at +50 mV (Fig. 2, A and B, and Table 1)."
37898402
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"These results strongly suggested that Y71 functions as a “gate-keeper” residue, restricting access of imipramine to the PAS domain cavity.To further investigate if the charge at position 71 may have an effect on EAG1 current inhibition by imipramine, Y71 was substituted for either glutamate or arginine."
37898402
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"Residues D39 and R84 located in the PAS domain cavity are essential for EAG1 current inhibition by imipramine."
37898402
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"Importantly, for both the PAS domain deletion and D39G/R84G mutation, EAG1 currents were still inhibited by imipramine, although with a two-fold higher IC (Table 1)."
37898402
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"It has been shown that imipramine also inhibits EAG1 channels in a voltage-dependent manner and competes for this inhibition with an open-pore channel blocker TEA (27)."
37898402
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"We hope that the molecular mechanism of imipramine inhibition uncovered in our study will facilitate the development of EAG1 channel-specific small molecule inhibitors that bind to their intracellular PAS domains and can be used for the treatment of cancer and neurological disorders associated with defects in EAG1 channel function.The IC value for imipramine inhibition of WT EAG1 channels determined with TEVC (∼60 μM) was higher than the IC determined for EAG1 currents recorded from HEK293 in the whole-cell configuration (∼2 μM) (27)."
37898402
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"Inhibition of hEag1 by imipramine and mAb56 reduced the migration of HEL and PLB-985 cells up to 65%, indicating an implication of the channel activity in this phenomenon."
20105281
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"Imipramine, a tryciclic antidepressant and the antihistamine astemizole inhibit eag1 [52,53] ; imipramine impairs cell proliferation in human melanoma cell lines expressing eag1 [52] ."
16473665
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"Dose dependent Inhibition of hEag1 Currents by Imipramine and Astemizole."
15365094
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"HEag1 channels recorded in these conditions were blocked by bath applications of imipramine (XREF_FIG A) and astemizole (XREF_FIG B)."
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