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G protein-coupled receptor kinase 2-mediated phosphorylation of downstream regulatory element antagonist modulator regulates membrane trafficking of Kv4.2 potassium channel

Ruiz-Gomez, Ana; Mellström, Britt; Tornero, Daniel LU ; Morato, Esperanza; Savignac, Magali; Holguín, Helena; Aurrekoetxea, Koldo; González, Paz; González-García, Carmen and Ceña, Valentín, et al. (2007) In Journal of Biological Chemistry 282(2). p.15-1205
Abstract

Downstream regulatory element antagonist modulator (DREAM)/potassium channel interacting protein (KChIP3) is a multifunctional protein of the neuronal calcium sensor subfamily of Ca2+-binding proteins with specific roles in different cell compartments. In the nucleus, DREAM acts as a Ca2+-dependent transcriptional repressor, and outside the nucleus DREAM interacts with Kv4 potassium channels, regulating their trafficking to the cell membrane and their gating properties. In this study we characterized the interaction of DREAM with GRK6 and GRK2, members of the G protein-coupled receptor kinase family of proteins, and their phosphorylation of DREAM. Ser-95 was identified as the site phosphorylated by GRK2. This phosphorylation did not... (More)

Downstream regulatory element antagonist modulator (DREAM)/potassium channel interacting protein (KChIP3) is a multifunctional protein of the neuronal calcium sensor subfamily of Ca2+-binding proteins with specific roles in different cell compartments. In the nucleus, DREAM acts as a Ca2+-dependent transcriptional repressor, and outside the nucleus DREAM interacts with Kv4 potassium channels, regulating their trafficking to the cell membrane and their gating properties. In this study we characterized the interaction of DREAM with GRK6 and GRK2, members of the G protein-coupled receptor kinase family of proteins, and their phosphorylation of DREAM. Ser-95 was identified as the site phosphorylated by GRK2. This phosphorylation did not modify the repressor activity of DREAM. Mutation of Ser-95 to aspartic acid, however, blocked DREAM-mediated membrane expression of the Kv4.2 potassium channel without affecting channel tetramerization. Treatment with the calcineurin inhibitors FK506 and cyclosporin A also blocked DREAM-mediated Kv4.2 channel trafficking and calcineurin de-phosphorylated GRK2-phosphorylated DREAM in vitro. Our results indicate that these two Ca2+-dependent posttranslational events regulate the activity of DREAM on Kv4.2 channel function.

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@misc{d6677306-0818-4389-897a-1610261fbde4,
  abstract     = {<p>Downstream regulatory element antagonist modulator (DREAM)/potassium channel interacting protein (KChIP3) is a multifunctional protein of the neuronal calcium sensor subfamily of Ca2+-binding proteins with specific roles in different cell compartments. In the nucleus, DREAM acts as a Ca2+-dependent transcriptional repressor, and outside the nucleus DREAM interacts with Kv4 potassium channels, regulating their trafficking to the cell membrane and their gating properties. In this study we characterized the interaction of DREAM with GRK6 and GRK2, members of the G protein-coupled receptor kinase family of proteins, and their phosphorylation of DREAM. Ser-95 was identified as the site phosphorylated by GRK2. This phosphorylation did not modify the repressor activity of DREAM. Mutation of Ser-95 to aspartic acid, however, blocked DREAM-mediated membrane expression of the Kv4.2 potassium channel without affecting channel tetramerization. Treatment with the calcineurin inhibitors FK506 and cyclosporin A also blocked DREAM-mediated Kv4.2 channel trafficking and calcineurin de-phosphorylated GRK2-phosphorylated DREAM in vitro. Our results indicate that these two Ca2+-dependent posttranslational events regulate the activity of DREAM on Kv4.2 channel function.</p>},
  author       = {Ruiz-Gomez, Ana and Mellström, Britt and Tornero, Daniel and Morato, Esperanza and Savignac, Magali and Holguín, Helena and Aurrekoetxea, Koldo and González, Paz and González-García, Carmen and Ceña, Valentín and Mayor, Federico and Naranjo, Jose R},
  issn         = {0021-9258},
  keyword      = {Calcineurin,Calcium,Cell Line,Cell Membrane,G-Protein-Coupled Receptor Kinase 2,G-Protein-Coupled Receptor Kinases,Humans,Kidney,Kv Channel-Interacting Proteins,Leucine,Phosphorylation,Protein Structure, Quaternary,Protein Transport,Protein-Serine-Threonine Kinases,Repressor Proteins,Shal Potassium Channels,Substrate Specificity,Transcription, Genetic,Two-Hybrid System Techniques,beta-Adrenergic Receptor Kinases},
  language     = {eng},
  month        = {01},
  number       = {2},
  pages        = {15--1205},
  publisher    = {ARRAY(0xb414518)},
  series       = {Journal of Biological Chemistry},
  title        = {G protein-coupled receptor kinase 2-mediated phosphorylation of downstream regulatory element antagonist modulator regulates membrane trafficking of Kv4.2 potassium channel},
  url          = {http://dx.doi.org/10.1074/jbc.M607166200},
  volume       = {282},
  year         = {2007},
}