Journal of Biological Chemistry
Volume 287, Issue 35, 24 August 2012, Pages 29815-29824
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Signal Transduction
The A-kinase Anchoring Protein Yotiao Facilitates Complex Formation between Adenylyl Cyclase Type 9 and the IKs Potassium Channel in Heart*

https://doi.org/10.1074/jbc.M112.380568Get rights and content
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The scaffolding protein Yotiao is a member of a large family of protein A-kinase anchoring proteins with important roles in the organization of spatial and temporal signaling. In heart, Yotiao directly associates with the slow outward potassium ion current (IKs) and recruits both PKA and PP1 to regulate IKs phosphorylation and gating. Human mutations that disrupt IKs-Yotiao interaction result in reduced PKA-dependent phosphorylation of the IKs subunit KCNQ1 and inhibition of sympathetic stimulation of IKs, which can give rise to long-QT syndrome. We have previously identified a subset of adenylyl cyclase (AC) isoforms that interact with Yotiao, including AC1–3 and AC9, but surprisingly, this group did not include the major cardiac isoforms AC5 and AC6. We now show that either AC2 or AC9 can associate with KCNQ1 in a complex mediated by Yotiao. In transgenic mouse heart expressing KCNQ1-KCNE1, AC activity was specifically associated with the IKs-Yotiao complex and could be disrupted by addition of the AC9 N terminus. A survey of all AC isoforms by RT-PCR indicated expression of AC4–6 and AC9 in adult mouse cardiac myocytes. Of these, the only Yotiao-interacting isoform was AC9. Furthermore, the endogenous IKs-Yotiao complex from guinea pig also contained AC9. Finally, AC9 association with the KCNQ1-Yotiao complex sensitized PKA phosphorylation of KCNQ1 to β-adrenergic stimulation. Thus, in heart, Yotiao brings together PKA, PP1, PDE4D3, AC9, and the IKs channel to achieve localized temporal regulation of β-adrenergic stimulation.

Adenylate Cyclase (Adenylyl Cyclase)
cAMP
Heart
Potassium Channels
Protein Kinase A (PKA)
A-kinase Anchoring Protein (AKAP)
KCNQ1
Yotiao

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*

This work was supported, in whole or in part, by National Institutes of Health Grants GM60419 (to C. W. D.) and HL044365 (to R. S. K.). This work was also supported by American Heart Association Grant GRNT2200034 (to C. W. D.).