Regulatory actions of the A-kinase anchoring protein Yotiao on a heart potassium channel downstream of PKA phosphorylation.
A-kinase anchoring proteins (AKAPs) are thought to be passive members of protein complexes that coordinate the association of cAMP-dependent protein kinase A (PKA) with cellular substrates to facilitate targeted PKA protein phosphorylation. I(Ks), the slow heart potassium current, is carried by the I(Ks) potassium channel, a substrate for PKA phosphorylation in response to sympathetic nerve stimulation, is a macromolecular complex that includes the KCNQ1 alpha subunit, the KCNE1 regulatory subunit, and the AKAP Yotiao. Disruption of this regulation by mutation in the long QT syndrome is associated with elevated risk of sudden death. Here, we have studied the effects of the AKAP Yotiao on the function of the I(Ks) channel that had been mutated to simulate channel phosphorylation, and we report direct AKAP-mediated alteration of channel function distinct from its role in the coordination of channel phosphorylation by PKA. These data reveal previously undescribed actions of Yotiao that occur subsequent to channel phosphorylation and provide evidence that this adaptor protein also may serve as an effector in regulating this important ion channel.
Kurokawa
Junko
J
Department of Pharmacology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
Motoike
Howard K
HK
Rao
Jenny
J
Kass
Robert S
RS
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D016297:Mutagenesis, Site-Directed; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011994:Recombinant Proteins; D004247:DNA; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases