Dopamine D2 receptor relies upon PPM/PP2C protein phosphatases to dephosphorylate huntingtin protein

J Biol Chem. 2014 Apr 25;289(17):11715-11724. doi: 10.1074/jbc.M113.544312. Epub 2014 Mar 11.

Abstract

Striatal dopamine D2 receptor (D2R) relies upon G protein- and β-arrestin-dependent signaling pathways to convey its action on motor control and behavior. Considering that D2R activation inhibits Akt in the striatum and that huntingtin physiological functions are affected by Akt phosphorylation, we sought to investigate whether D2R-mediated signaling could regulate huntingtin phosphorylation. We demonstrate that D2R activation decreases huntingtin phosphorylation on its Akt site. This dephosphorylation event depends upon the Gαi-dependent engagement of specific members of the protein phosphatase metallo-dependent (PPM/PP2C) family and is independent of β-arrestin 2. These observations identify the PPM/PP2C family as a mediator of G protein-coupled receptor signaling and thereby suggest a novel mechanism of dopaminergic signaling.

Keywords: Akt; Arrestin; Dopamine D2 Receptor; Dopamine Receptors; G Protein-coupled Receptors (GPCR); G Proteins; Huntingtin; PP2C; Phosphatase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • HEK293 Cells
  • Humans
  • Huntingtin Protein
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Dopamine D2 / metabolism*

Substances

  • Htt protein, mouse
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Receptors, Dopamine D2
  • Proto-Oncogene Proteins c-akt
  • Phosphoprotein Phosphatases