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Vol. 17, Issue 11, 4666-4674, November 2006

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Association of 14-3-3 Proteins to ₁-Adrenergic Receptors Modulates Kv11.1 K⁺ Channel Activity in Recombinant Systems

Antonio S. Tutor^*, Eva Delpón, Ricardo Caballero, Ricardo Gómez, Lucía Núñez, Miguel Vaquero, Juan Tamargo, Federico Mayor, Jr.^*, and Petronila Penela^*

*Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa," Universidad Autónoma de Madrid, 28049 Madrid, Spain; and Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain

Submitted May 17, 2006; Revised July 31, 2006; Accepted August 8, 2006
Monitoring Editor: J. Silvio Gutkind

We identify a new mechanism for the ₁-adrenergic receptor (₁AR)-mediated regulation of human ether-a-go-go–related gene (HERG) potassium channel (Kv11.1). We find that the previously reported modulatory interaction between Kv11.1 channels and 14-3-3 proteins is competed by wild type ₁AR by means of a novel interaction between this receptor and 14-3-3. The association between ₁AR and 14-3-3 is increased by agonist stimulation in both transfected cells and heart tissue and requires cAMP-dependent protein kinase (PKA) activity. The ₁AR/14-3-3 association is direct, since it can be recapitulated using purified 14-3-3 and ₁AR fusion proteins and is abolished in cells expressing ₁AR phosphorylation–deficient mutants. Biochemical and electrophysiological studies of the effects of isoproterenol on Kv11.1 currents recorded using the whole-cell patch clamp demonstrated that ₁AR phosphorylation–deficient mutants do not recruit 14-3-3 away from Kv11.1 and display a markedly altered agonist-mediated modulation of Kv11.1 currents compared with wild-type ₁AR, increasing instead of inhibiting current amplitudes. Interestingly, such differential modulation is not observed in the presence of 14-3-3 inhibitors. Our results suggest that the dynamic association of 14-3-3 proteins to both ₁AR and Kv11.1 channels is involved in the adrenergic modulation of this critical regulator of cardiac repolarization and refractoriness.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-05-0422) on August 16, 2006.

Address correspondence to: Federico Mayor, Jr. (fmayor{at}cbm.uam.es)

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