Yotiao, More Than a Passive Scaffold

Abstract

Yotiao is an A-kinase anchoring protein (AKAP) that, in the heart, mediates the formation of a macromolecular complex consisting of the I Ks channel (α subunit KCNQ1 and regulatory subunit KCNE1), protein kinase A (PKA), and protein phosphatase 1 (PP1). Mutations that disrupt this complex do not allow the channel to be regulated in response to stress and can cause death. The effects of PKA on the channel can be mimicked by mutation of Ser 97 to Asp in the KCNQ1 subunit. Using cells transfected with this mutant form of the channel, Kurokawa et al. demonstrated that interaction with Yotiao increased channel current by slowing channel inactivation in the absence of adenosine 3′,5′-monophosphate (cAMP). This effect of Yotiao on the S97D channel was not blocked by inhibitors of PKA or protein kinase C (PKC), which indicates that Yotiao was not promoting phosphorylation of other sites on the channel. Disruption of the Yotiao interaction by mutation of the KCNQ1 leucine zipper domain blocked the ability of Yotiao to slow channel deactivation. Yotiao did not alter channel kinetics in the absence of cAMP in the cells expressing the wild-type channel, which suggests that Yotiao not only may promote PKA phosphorylation of the channel but also may depend on this phosphorylation to exert the subsequent effects on channel deactivation kinetics. Thus, Yotiao may provide more than a scaffolding function in regulation of the I Ks channel. J. Kurokawa, H. K. Motoike, J. Rao, R. S. Kass, Regulatory actions of the A-kinase anchoring protein Yotiao on a heart potassium channel downstream of PKA phosphorylation. Proc. Natl. Acad. Sci. U.S.A. 101 , 16374-16378 (2004). [Abstract] [Full Text]