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J. Biol. Chem., Vol. 283, Issue 23, 15672-15680, June 6, 2008

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Phosphorylation-dependent Binding of 14-3-3 Proteins Controls TRESK Regulation^*

From the Department of Physiology, Semmelweis University, H-1444 Budapest, Hungary

The two-pore domain K⁺ channel, TRESK (TWIK-related spinal cord K⁺ channel) is reversibly activated by the calcium/calmodulin-dependent protein phosphatase, calcineurin. In the present study, we report that 14-3-3 proteins directly bind to the intracellular loop of TRESK and control the kinetics of the calcium-dependent regulation of the channel. Coexpression of 14-3-3 with TRESK blocked, whereas the coexpression of a dominant negative form of 14-3-3 accelerated the return of the K⁺ current to the resting state after the activation mediated by calcineurin in Xenopus oocytes. The direct action of 14-3-3 was spatially restricted to TRESK, since 14-3-3 was also effective, when it was tethered to the channel by a flexible polyglutamine-containing chain. The effect of both the coexpressed and chained 14-3-3 was alleviated by the microinjection of Ser(P)-Raf259 phosphopeptide that competes with TRESK for binding to 14-3-3. The and isoforms of 14-3-3 controlled TRESK regulation, whereas the β, , , , and isoforms failed to influence the mechanism significantly. Phosphorylation of serine 264 in mouse TRESK was required for the binding of 14-3-3. Because 14-3-3 proteins are ubiquitous, they are expected to control the duration of calcineurin-mediated TRESK activation in all the cell types that express the channel, depending on the phosphorylation state of serine 264. This kind of direct control of channel regulation by 14-3-3 is unique within the two-pore domain K⁺ channel family.

Received for publication, January 28, 2008 , and in revised form, April 3, 2008.

^* This work was supported by the Hungarian National Research Fund (OTKA F-67743), by the Hungarian Medical Research Council (ETT-417/2006), and by a Semmelweis University research grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1 and Figs. S1 and S2. The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) EU267939 [GenBank] and EU267940.

¹ To whom correspondence should be addressed: Dept. of Physiology, Semmelweis University, P. O. Box 259, H-1444 Budapest, Hungary. Tel.: 36-1-266-2755/4079; Fax: 36-1-266-7480; E-mail: enyedi{at}puskin.sote.hu.

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