Regulatory actions of the A-kinase anchoring protein Yotiao on a heart potassium channel downstream of PKA phosphorylation

Department of Pharmacology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032

Edited by Ramon Latorre, Center for Scientific Studies, Valdivia, Chile, and approved October 4, 2004 (received for review July 31, 2004)

Abstract

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 postassium 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 α 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.

Footnotes

↵ * To whom correspondence should be addressed. E-mail: rsk20{at}columbia.edu.
Author contributions: J.K. and R.S.K. designed research; J.K. performed research; H.K.M. and J.R. contributed new reagents/analytic tools; J.K. and R.S.K. analyzed data; and J.R. and R.S.K. wrote the paper.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: AKAP, A-kinase anchoring protein; CHO, Chinese hamster ovary; LZ, leucine zipper; OA, okadaic acid; PKA, protein kinase A.
Freely available online through the PNAS open access option.