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• W2912048545 abstract "KCNQ1 voltage-gated potassium channel assembles with its KCNE1 auxiliary subunit to form the slow delayed rectifier (IKs) channel, which accelerates the repolarization of action potentials in cardiac myocytes. Loss-of-function mutations of KCNQ1 gene have been associated with long QT (LQT) syndrome and lead to an elevated risk of fatal cardiac arrhythmias. The activation of IKs channel depends on its physiological activator, phosphatidylinositol 4,5-bisphosphate (PIP2). In this study, we docked the previously identified PIP2 binding sites in a homology model of KCNQ1 and developed an in-silico screening to the Available Chemical Database. One of the hit compounds, CP1, potently increases the amplitude of IKs current (EC50=7.2 μM) heterogenously expressed in Xenopus oocytes and makes the channel constitutively open. Long intervals between voltage clamp pulses revealed that 2 μM CP1 slowed the deactivation of IKs channel by 13-fold. The half-point for activation was ∼40 mV more negative than wild-type channels. Further studies in guinea pig ventricular myocytes showed that 0.2 μM CP1 apparently shortens the prolonged action potential duration. In addition, CP1 is capable of rescuing the loss of IKs current caused by PIP2 depletion, suggesting that CP1 substitutes for PIP2 in activating IKs channels. Our results indicate that CP1 is a novel IKs channel opener and may provide a novel therapy to treat congential and acquired LQT syndromes." @default.
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• W2912048545 date "2019-02-01" @default.
• W2912048545 modified "2023-09-30" @default.
• W2912048545 title "CP1 Is a Potent IKs Channel Activator Which Acts by Substituting Phosphatidylinositol 4,5 Bisphosphate" @default.
• W2912048545 doi "https://doi.org/10.1016/j.bpj.2018.11.2916" @default.
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