Modulation of GABAA Receptor Phosphorylation and Membrane Trafficking by Phospholipase C-related Inactive Protein/Protein Phosphatase 1 and 2A Signaling Complex Underlying Brain-derived Neurotrophic Factor-dependent Regulation of GABAergic Inhibition

TNF-α Downregulates Inhibitory Neurotransmission through Protein Phosphatase 1-Dependent Trafficking of GABAAReceptors

“…Lastly, we found that calcineurin activity (blocked with cyclosporin A) was not required in this signaling pathway (cyclosporin A alone, 90.2 Ϯ 9.1% of DMSO alone; cyclosporin A ϩ TNF␣, 60.2 Ϯ 3.3% of DMSO alone). Because PP1/PP2A activity has been implicated previously in GABA A R endocytosis Kanematsu et al, 2006Kanematsu et al, , 2007Lin et al, 2011) whereas calcineurin activity has been implicated in GABA A R cluster dispersal (Bannai et al, 2009;Muir et al, 2010), our findings are again consistent with an endocytosis-dependent effect.…”

“…Previous studies have suggested that an increased abundance of protein phosphatase associated with the GABA A R protein complex correlates with increased dephosphorylation of ␤3 and subsequent endocytosis of GABA A Rs Kanematsu et al, 2006). The association of PP1 and PP2A with the ␤3 subunit is facilitated by the adaptor/regulatory proteins PRIP-1 and PRIP-2, which selectively bind to the intracellular domains of ␤1-␤3 subunits but not ␣1-␣3 or ␥2 subunits (Terunuma et al, 2004;Kanematsu et al, 2006Kanematsu et al, , 2007Yanagihori et al, 2006). We used coimmunoprecipitation to determine whether the association of ␤3 with the catalytic subunits of PP1 (PP1␣) or PP2A (PP2Ac) was regulated by TNF␣ (Fig.…”

“…At hippocampal synapses, GABA A Rs are composed of combinations of two ␣1-␣3 subunits, two ␤1-␤3 subunits, and one ␥2 subunit (Brünig et al, 2002;Michels and Moss, 2007;Olsen and Sieghart, 2009;Kasugai et al, 2010). We used cell-surface immunostaining to determine whether TNF␣ preferentially endocytoses certain receptor subtypes ( Fig.…”

Phospholipase C-related but Catalytically Inactive Protein (PRIP) Modulates Synaptosomal-associated Protein 25 (SNAP-25) Phosphorylation and Exocytosis

“…We isolated PRIP as a novel inositol 1,4,5-trisphosphate/PtdIns(4,5)P 2 -binding protein (23,32,34,35) and later identified it also as a protein phosphatase (PP1 and PP2A)-anchoring protein (29,30). Furthermore, very recently we found that PRIP associates with Akt when it is phosphorylated to be active (31), indicating that PRIP is a unique molecule participating in phosphorylation events from both sides.…”

“…Further studies revealed that PRIP has a number of binding partners, including the catalytic subunit of protein phosphatase 1␣ (PP1␣) and PP2A (29,30) and the phosphorylated (active) form of Akt (31) in addition to Ins(1,4,5)P 3 and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2 ) (32)(33)(34)(35)(36). Thus, PRIP is a unique molecule that associates with both multiple phosphatases (PP1 and PP2A) and a kinase (activated form of Akt), suggesting that PRIP participates in the phospho-regulation of cellular events, by recruiting these enzymes to where the event occurs if PRIP can approach.…”