Direct interaction of PP2A phosphatase with GABAB receptors alters functional signaling

Xiaofan Li, Miho Terunuma, Tarek G. Deeb, Shari Wiseman, Menelas N. Pangalos, Angus C. Nairn, Stephen J. Moss, Paul A. Slesinger

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Addictive drugs usurp the brain’s intrinsic mechanism for reward, leading to compulsive and destructive behaviors. In the ventral tegmental area (VTA), the center of the brain’s reward circuit, GABAergic neurons control the excitability of dopamine (DA) projection neurons and are the site of initial psychostimulant-dependent changes in signaling. Previous work established that cocaine/methamphetamine exposure increases protein phosphatase 2A (PP2A) activity, which dephosphorylates the GABABR2 subunit, promotes internalization of the GABAB receptor (GABABR) and leads to smaller GABABR-activated G-protein-gated inwardly rectifying potassium (GIRK) currents in VTA GABA neurons. How the actions of PP2A become selective for a particular signaling pathway is poorly understood. Here, we demonstrate that PP2A can associate directly with a short peptide sequence in the C terminal domain of the GABABR1 subunit, and that GABABRs and PP2A are in close proximity in rodent neurons (mouse/rat; mixed sexes). We show that this PP2AGABABR interaction can be regulated by intracellular Ca2 +. Finally, a peptide that potentially reduces recruitment of PP2A to GABABRs and thereby limits receptor dephosphorylation increases the magnitude of baclofen-induced GIRK currents. Thus, limiting PP2Adependent dephosphorylation of GABABRs may be a useful strategy to increase receptor signaling for treating diseases.

Original languageEnglish
Pages (from-to)2808-2816
Number of pages9
JournalJournal of Neuroscience
Issue number14
StatePublished - 1 Apr 2020


  • GABA(B)
  • GIRK
  • Inhibition
  • PLA
  • Phosphatase
  • Trafficking


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