Direct interaction of PP2A phosphatase with GABA_B receptors alters functional signaling

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 GABA_BR2 subunit, promotes internalization of the GABA_B receptor (GABA_BR) and leads to smaller GABA_BR-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 GABA_BR1 subunit, and that GABA_BRs and PP2A are in close proximity in rodent neurons (mouse/rat; mixed sexes). We show that this PP2AGABA_BR interaction can be regulated by intracellular Ca^{2 +}. Finally, a peptide that potentially reduces recruitment of PP2A to GABA_BRs and thereby limits receptor dephosphorylation increases the magnitude of baclofen-induced GIRK currents. Thus, limiting PP2Adependent dephosphorylation of GABA_BRs may be a useful strategy to increase receptor signaling for treating diseases.