Mechanisms of Fast Desensitization of GABAB Receptor-Gated Currents

Raveh, Adi; Tureček, Rostislav; Bettler, Bernhard

doi:10.1016/bs.apha.2014.11.004

Cited by 7 publications

(1 citation statement)

References 120 publications

(186 reference statements)

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“…GABA B Rs undergo agonist-induced desensitization, as well as cross-desensitization induced by activation of other receptors. Desensitization involves relatively fast processes at the level of G-protein signaling and a slower process of receptor endocytosis (Raveh et al, 2015). GABA B Rs are known to undergo constitutive endocytosis, followed by either degradation or recycling back to the plasma membrane (Vargas et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Direct Interaction of PP2A Phosphatase with GABA_BReceptors Alters Functional Signaling

Terunuma

Deeb

et al. 2020

J. Neurosci.

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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 B R2 subunit, promotes internalization of the GABA B receptor (GABA B R) and leads to smaller GABA B 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 GABA B R1 subunit, and that GABA B Rs and PP2A are in close proximity in rodent neurons (mouse/rat; mixed sexes). We show that this PP2A-GABA B R interaction can be regulated by intracellular Ca 2ϩ. Finally, a peptide that potentially reduces recruitment of PP2A to GABA B Rs and thereby limits receptor dephosphorylation increases the magnitude of baclofen-induced GIRK currents. Thus, limiting PP2Adependent dephosphorylation of GABA B Rs may be a useful strategy to increase receptor signaling for treating diseases.

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Section: Introductionmentioning

confidence: 99%