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

The subunits KCNQ1 and KCNE1 generate the slowly activating, delayed rectifier potassium current, I_Ks, that responds to sympathetic stimulation and is critical for human cardiac repolarization. The A-kinase anchoring protein Yotiao facilitates macromolecular complex formation between I_Ks and protein kinase A to regulate phosphorylation of KCNQ1 and I_Ks currents following beta-adrenergic stimulation. We have previously shown that adenylyl cyclase Type 9 (AC9) is associated with a complex and facilitates isoproterenol-stimulated phosphorylation of KCNQ1 in an immortalized cell line. However, requirement for AC9 in sympathetic control of I_Ks in the heart was unknown. Using a transgenic mouse strain expressing the KCNQ1-KCNE1 subunits of I_Ks, 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 I_Ks currents was also observed in adult cardiomyocytes from I_Ks-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 phosphorylation of KCNQ1 in vivo and for functional regulation of I_Ks in adult cardiomyocytes.

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