The A-kinase anchoring protein Yotiao facilitates complex formation between adenylyl cyclase type 9 and the IKs potassium channel in heart.
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 (I(Ks)) and recruits both PKA and PP1 to regulate I(Ks) phosphorylation and gating. Human mutations that disrupt I(Ks)-Yotiao interaction result in reduced PKA-dependent phosphorylation of the I(Ks) subunit KCNQ1 and inhibition of sympathetic stimulation of I(Ks), 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 I(Ks)-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 I(Ks)-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 I(Ks) channel to achieve localized temporal regulation of β-adrenergic stimulation.
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Yong
Y
Li
Lei
L
Chen
Robert S
RS
Kass
Carmen W
CW
Dessauer
D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*
D054758:A Kinase Anchor Proteins; C119719:AKAP9 protein, human; D003598:Cytoskeletal Proteins; C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; C092068:Kcne1 protein, mouse; C496910:Kcnq1 protein, mouse; D046912:Multiprotein Complexes; D009124:Muscle Proteins; D024642:Potassium Channels, Voltage-Gated; D017868:Cyclic AMP-Dependent Protein Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D000262:Adenylyl Cyclases; C413923:adenylate cyclase 9; C100622:adenylyl cyclase 2