PKCβII specifically regulates KCNQ1/KCNE1 channel membrane localization.

The slow voltage-gated potassium channel (IKs) is composed of the KCNQ1 and KCNE1 subunits and is one of the major repolarizing currents in the heart. Activation of protein kinase C has been linked to cardiac arrhythmias. Although has been shown to be a regulator of a number of cardiac channels, including IKs, little is known about regulation of the channel by specific isoforms of Here we studied the role of different duanyu1531 isoforms on IKs channel membrane localization and function. Our studies focused on duanyu1531 isoforms that translocate to the plasma membrane in response to Gq-coupled receptor (GqPCR) stimulation: and Prolonged stimulation of GqPCRs has been shown to decrease IKs membrane expression, but the specific role of each duanyu1531 isoform is unclear. Here we show that stimulation of calcium-dependent isoforms of duanyu1531 but not mimic receptor activation. In addition, we show that general (LY-333531) and duanyu1531βII inhibitors but not or inhibitors blocked the effect of on the KCNQ1/KCNE1 channel. duanyu1531β inhibitors also blocked GqPCR-mediated decrease in channel membrane expression in cardiomyocytes. Direct activation of duanyu1531βII using constitutively active duanyu1531βII construct mimicked agonist-induced decrease in membrane expression and channel function, while dominant negative duanyu1531βII showed no effect. This suggests that the KCNQ1/KCNE1 channel was not regulated by basal levels of duanyu1531βII activity. Our results indicate that duanyu1531βII is a specific regulator of IKs membrane localization. duanyu1531βII expression and activation are strongly increased in many disease states, including heart disease and diabetes. Thus, our results suggest that duanyu1531βII inhibition may protect against acquired QT prolongation associated with heart disease.

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