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Effects of the Ras homolog Rhes on Akt/protein kinase B and glycogen synthase kinase 3 phosphorylation in striatum

L M Harrison1, S H Muller, D Spano

  • 1Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA. lhar14@lsuhsc.edu

Neuroscience
|February 6, 2013
PubMed

Insights

Rhes protein is crucial for dopamine D2 receptor signaling in the striatum. Its absence leads to increased Akt phosphorylation, mimicking lithium

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • G protein-coupled receptors (GPCRs) utilize diverse signaling pathways beyond heterotrimeric G proteins.
  • Dopamine D2 receptors in the striatum engage alternate pathways involving β-arrestin2, protein phosphatase 2A (PP2A), and Akt, regulating Akt phosphorylation.
  • Lithium disrupts this multi-protein complex, leading to increased Akt phosphorylation.

Purpose of the Study:

  • To investigate the role of Rhes, a striatally enriched GTP-binding protein, in dopamine receptor-mediated Akt/GSK3 signaling.
  • To determine if Rhes influences the multi-protein complex involved in Akt dephosphorylation.

Main Methods:

  • Utilized Rhes knockout (Rhes(-/-)) and wild-type (rhes(+/+)) mice.
  • Administered lithium and apomorphine (D1/D2 agonist) to assess Akt and GSK3β phosphorylation.
  • Employed co-immunoprecipitation to examine protein-protein interactions within the signaling complex.

Main Results:

  • Rhes(-/-) mice exhibited elevated basal Akt and GSK3β phosphorylation, unaffected by lithium.
  • Apomorphine increased Akt and GSK3 phosphorylation in Rhes(-/-) mice, recruiting PP2A-C to Akt.
  • Rhes co-immunoprecipitated with β-arrestins, indicating its integral role in the multi-protein complex.

Conclusions:

  • Rhes is essential for the striatal multi-protein complex to dephosphorylate Akt.
  • The absence of Rhes results in a phenotype resembling lithium treatment, with constitutively high Akt phosphorylation.
  • Rhes modulates dopamine receptor signaling through the Akt/GSK3 pathway.

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