IndraLab

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KB130015 activates KCNH2. 9 / 9
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"We conclude that KB130015 activates hERG1 channels via a novel mechanism that is not directed to removal of inactivation or to slow-down of deactivation but rather involves an acceleration of hERG1 activation."
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"As shown in XREF_FIG, hERG1 activation is significantly accelerated by KB130015 in a voltage dependent manner (e.g., 3.8-fold at -20 mV compared to 2.4-fold at +40 mV)."
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"We assume that KB130015 mediated hERG1 activation depends on conformational transitions that require a tyrosine at position 652."
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"Increasing KB130015 concentrations enhanced hERG1 outward current amplitudes at -20 mV (XREF_FIG)."
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"We conclude that MTx and KB130015 synergically activate hERG1 channels, requiring the existence of at least two functionally coupled activator sites."
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"KB130015 accelerates hERG1 activation gating."
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"KB130015 activates and blocks hERG1 channels independently of inactivation gating."
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"While we can not exclude that KB130015 binding in the central cavity partly underlies the inhibitory effects of KB130015 and its competition with pore blockers, the lack of use-dependence for hERG1 activation by KB130015 requires an " activator " site outside the inner cavity."
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"The effective concentration in the micromolar range of hERG1 activation by KB130015 is comparable to that of RPR260243, NS1643, and PD-118057, whereas mallotoxin, the only known natural hERG1 activator, is active even in the sub-micromolar range."
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