Direct interaction of PP2A phosphatase with GABA B 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
Journal of Neuroscience 2020 February 26
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 GABAB R2 subunit, promotes internalization of the GABAB receptor and leads to smaller GABAB R-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 GABAB R1 subunit, and that GABAB Rs and PP2A are in close proximity in rodent neurons (mouse/rat; mixed sexes). We show that this PP2A-GABAB R interaction can be regulated by intracellular Ca2+ Finally, a peptide that potentially reduces recruitment of PP2A to GABAB Rs and thereby limits receptor dephosphorylation increases the magnitude of baclofen-induced GIRK currents. Thus, limiting PP2A-dependent dephosphorylation of GABAB Rs may be a useful strategy to increase receptor signaling for treating diseases.Significance Statement:Dysregulation of GABAB receptors underlie some of the altered neurotransmission in many neurological disorders. Protein phosphatase 2A (PP2A) is involved in dephosphorylating and subsequent internalization of GABAB receptors in models of addiction and depression. Here, we provide new evidence that PP2A B55 regulatory subunit interacts directly with a small region of the C-terminal domain of the GABAB R1 subunit, and that this interaction is sensitive to intracellular Ca2+ We demonstrate that a short peptide corresponding to the PP2A interaction site on GABAB R1 competes for PP2A binding, enhances phosphorylation GABAB R2 S783, and affects functional signaling through GIRK channels. Our study highlights how targeting PP2A dependent dephosphorylation of GABAB Rs may provide a specific strategy to modulate GABAB R signaling in disease conditions.

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