Regulation of IKs Potassium Current by Isoproterenol in Adult Cardiomyocytes Requires Type 9 Adenylyl Cyclase.

Yong Li,Lei Chen,Thomas Hof,Tanya A Baldwin,Robert S Kass,Carmen W Dessauer

doi:10.3390/cells8090981

Yong Li, Lei Chen + Show 4 more

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https://doi.org/10.3390/cells8090981

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Abstract

The subunits KCNQ1 and KCNE1 generate the slowly activating, delayed rectifier potassium current, IKs, that responds to sympathetic stimulation and is critical for human cardiac repolarization. The A-kinase anchoring protein Yotiao facilitates macromolecular complex formation between IKs and protein kinase A (PKA) to regulate phosphorylation of KCNQ1 and IKs currents following beta-adrenergic stimulation. We have previously shown that adenylyl cyclase Type 9 (AC9) is associated with a KCNQ1-Yotiao-PKA complex and facilitates isoproterenol-stimulated phosphorylation of KCNQ1 in an immortalized cell line. However, requirement for AC9 in sympathetic control of IKs in the heart was unknown. Using a transgenic mouse strain expressing the KCNQ1-KCNE1 subunits of IKs, we show that AC9 is the only adenylyl cyclase (AC) isoform associated with the KCNQ1-KCNE1-Yotiao complex in the heart. Deletion of AC9 resulted in the loss of isoproterenol-stimulated KCNQ1 phosphorylation in vivo, even though AC9 represents less than 3% of total cardiac AC activity. Importantly, a significant reduction of isoproterenol-stimulated IKs currents was also observed in adult cardiomyocytes from IKs-expressing AC9KO mice. AC9 and Yotiao co-localize with N-cadherin, a marker of intercalated disks and cell–cell junctions, in neonatal and adult cardiomyocytes, respectively. In conclusion, AC9 is necessary for sympathetic regulation of PKA phosphorylation of KCNQ1 in vivo and for functional regulation of IKs in adult cardiomyocytes.

Highlights

The slow delayed rectifier (IKs ) current in cardiomyocytes (CMs) is produced by a potassium channel composed of four KCNQ1 (Kv7.1) α-subunits along with the accessory KCNE1 (MinK) β-subunits [1,2].In the heart, this outward potassium channel is important for the repolarization late phase of the cardiac action potential and becomes more critical as sympathetic activity increases the heart rate [3]
Using a transgenic mouse strain that expresses the subunits of human IKs, KCNQ1-KCNE1, we show that knockout of adenylyl cyclase Type 9 (AC9) results in a complete loss of Yotiao- and KCNQ1-associated adenylyl cyclase (AC) activity
A functional IKs is largely absent in adult mice, we crossed the AC9 deletion with a transgenic strain containing cardiac-specific expression of hKCNQ1-hKCNE1 [5]

Summary

Introduction

The slow delayed rectifier (IKs ) current in cardiomyocytes (CMs) is produced by a potassium channel composed of four KCNQ1 (Kv7.1) α-subunits along with the accessory KCNE1 (MinK) β-subunits [1,2]. In the heart, this outward potassium channel is important for the repolarization late phase of the cardiac action potential and becomes more critical as sympathetic activity increases the heart rate [3]. Yotiao positions KCNQ1 near to PKA, and to termination signals such as phosphodiesterase PDE4D3 and the phosphatase PP1 [5,8]

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