Selective Regulation of NR2B by Protein Phosphatase-1 for the Control of the NMDA Receptor in Neuroprotection

Farinelli, Mélissa; Heitz, Fabrice D.; Grewe, Benjamin F.; Tyagarajan, Shiva K.; Helmchen, Fritjof; Mansuy, Isabelle M.

doi:10.1371/journal.pone.0034047

Cited by 20 publications

(15 citation statements)

References 59 publications

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“…; Farinelli et al . ) and may mediate the effect of CK1 inhibition, we determined whether PP1/PP2A is involved in the effect of CK1 inhibition on NMDAR activity in the PVN. Treatment of brain slices with tautomycetin (1 μ m , Tocris Bioscience, Bristol, UK), the specific PP1/2A inhibitor (Mitsuhashi et al .…”

Section: Resultsmentioning

confidence: 99%

Endogenous casein kinase‐1 modulates NMDA receptor activity of hypothalamic presympathetic neurons and sympathetic outflow in hypertension

Zhou

Pan

2015

The Journal of Physiology

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Key pointsr Increased NMDA receptor activity and excitability of presympathetic neurons in the hypothalamus can increase sympathetic nerve discharges leading to hypertension.r In this study, we determined how protein kinases and phosphatases are involved in regulating NMDA receptor activity and firing activity of presympathetic neurons in the hypothalamus in normotensive and hypertensive rats.r We show that casein kinase-1 inhibition increases NMDA receptor activity and excitability of presympathetic neurons in the hypothalamus and augments sympathetic nerve discharges in normotensive, but not in hypertensive, rats.r Our data indicate that casein kinase-1 tonically regulates NMDA receptor activity by interacting with casein kinase-2 and protein phosphatases in the hypothalamus and that imbalance of NMDA receptor phosphorylation can augment the excitability of hypothalamic presympathetic neurons and sympathetic nerve discharges in hypertension.r These findings help us understand the neuronal mechanism of hypertension, and reducing the NMDA receptor phosphorylation level may be effective for treating neurogenic hypertension.Abstract Increased N-methyl-D-aspartate receptor (NMDAR) activity in the paraventricular nucleus (PVN) of the hypothalamus is involved in elevated sympathetic outflow in hypertension. However, the molecular mechanisms underlying augmented NMDAR activity in hypertension remain unclear. In this study, we determined the role of casein kinase-1 (CK1) in regulating NMDAR activity in the PVN. NMDAR-mediated excitatory postsynaptic currents (EPSCs) and puff NMDA-elicited currents were recorded in spinally projecting PVN neurons in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. The basal amplitudes of evoked NMDAR-EPSCs and puff NMDA currents were significantly higher in SHRs than in WKY rats. The CK1 inhibitor PF4800567 or PF670462 significantly increased the amplitude of NMDAR-EPSCs and puff NMDA currents in PVN neurons in WKY rats but not in SHRs. PF4800567 caused an NMDAR-dependent increase in the excitability of PVN neurons only in WKY rats. Also, the CK1ε protein level in the PVN was significantly lower in SHRs than in WKY rats. Furthermore, intracerebroventricular infusion of PF4800567 increased blood pressure and lumbar sympathetic nerve activity in WKY rats, and this effect was eliminated by microinjection of the NMDAR antagonist into the PVN. In addition, PF4800567 failed to increase NMDAR activity in brain slices of WKY rats pretreated with the protein phosphatase 1/2A, calcineurin, or casein kinase-2 inhibitor. Our findings suggest that CK1 tonically suppresses NMDAR activity in the PVN by reducing the NMDAR phosphorylation level. Diminished CK1 activity may contribute to potentiated glutamatergic synaptic input to PVN presympathetic neurons and elevated sympathetic vasomotor tone in neurogenic hypertension. Abbreviations ABP, arterial blood pressure; aCSF, artificial cerebrospinal fluid; AMPA, α-amino-3-hydroxy-4-isoxazoleproprionic acid; AMPAR, AMPA receptor; CK1, cas...

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Section: Resultsmentioning

confidence: 99%

Endogenous casein kinase‐1 modulates NMDA receptor activity of hypothalamic presympathetic neurons and sympathetic outflow in hypertension

Zhou

Pan

2015

The Journal of Physiology

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“…; Farinelli et al . ), and PP1 targeting by neurabin and spinophilin is important for normal plasticity (Yan et al . ; Allen et al .…”

Section: Resultsmentioning

confidence: 99%

Differential association of postsynaptic signaling protein complexes in striatum and hippocampus

Baucum

Brown

Colbran

2012

Journal of Neurochemistry

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Distinct physiological stimuli are required for bidirectional synaptic plasticity in striatum and hippocampus, but differences in the underlying signaling mechanisms are poorly understood. We have begun to compare levels and interactions of key excitatory synaptic proteins in whole extracts and subcellular fractions isolated from micro-dissected striatum and hippocampus. Levels of multiple glutamate receptor subunits, calcium/calmodulin-dependent protein kinase II (CaMKII), a highly abundant serine/threonine kinase, and spinophilin, a F-actin and protein phosphatase 1 (PP1) binding protein, were significantly lower in striatal extracts, as well as in synaptic and/or extrasynaptic fractions, compared to similar hippocampal extracts/fractions. However, CaMKII interactions with spinophilin were more robust in striatum compared to hippocampus, and this enhanced association was restricted to the extrasynaptic fraction. NMDAR GluN2B subunits associate with both spinophilin and CaMKII, but spinophilin-GluN2B complexes were enriched in extrasynaptic fractions whereas CaMKII-GluN2B complexes were enriched in synaptic fractions. Notably, the association of GluN2B with both CaMKII and spinophilin was more robust in striatal extrasynaptic fractions compared to hippocampal extrasynaptic fractions. Selective differences in the assembly of synaptic and extrasynaptic signaling complexes may contribute to differential physiological regulation of excitatory transmission in striatum and hippocampus.

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“…Using yeast two‐hybrid screen and GST pull down assay, Ralf Enz revealed a direct association between PP1γ and glutamate receptor mGluR7b . Synaptic NMDA receptors recruit PP1α to mediated downstream aspects of synaptic signaling . The inhibition of PP1 results in a dysfunction in D(1A)DAR signal transmission in the prenatal cocaine‐exposed rabbit brain .…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, PP1γ‐mediated dephosphorylation of RIG‐I and MDA5 may also control the activation of NF‐κB . Moreover, studies revealed that neuronal receptors may directly recruit protein phosphatases, including PP1γ, to transmit downstream signals . These findings implicate an involvement of PP1γ in the regulation of cellular signaling and cancer cell physiology.…”

Section: Introductionmentioning

confidence: 98%

α7nAChR‐mediated recruitment of PP1γ promotes TRAF6/NF‐κB cascade to facilitate the progression of Hepatocellular Carcinoma

Wan

Zhang³

et al. 2018

Molecular Carcinogenesis

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The cholinergic signaling pathways have been recently implicated in the development of various human cancers. However, the underlying molecular mechanism remains largely unclear. In the present study, we reported that α7 nicotinic acetylcholine receptor (α7nAChR), an important member of nicotinic acetylcholine receptors, interacts with Protein Phosphatase-1γ (PP1γ) in human Hepatocellular Carcinoma (HCC) tissues. In addition, we found that α7nAChR facilitates the ubiquitination and activation of TRAF6 in a PP1γ-dependent manner in HCC cells. Furthermore, we showed that ligand-bounded α7nAChR induces the degradation of IκBα, leading to resultant phosphorylation and nuclear accumulation of NF-κB p65. Accordingly, acetylcholine triggers the expression of critical NF-κB target genes, such as Cyclin D1 and PCNA, as well as the proliferation of HCC cells in a PP1γ- and α7nAChR-dependent manner. Furthermore, we revealed that nicotine-triggered α7nAChR activation promotes oncosphere formation and in vivo tumor growth of HCC cells. Moreover, we showed that the protein levels of both α7nAChR and PP1γ are significantly upregulated in human HCC specimens compared with adjacent non-cancerous ones, and that upregulated expression of the two proteins predict significantly worsened prognosis in HCC patients. These findings together indicate that the cholinergic receptor α7nAChR exerts a facilitating role in HCC development through PP1γ-dependent TRAF6/NF-κB signaling.

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Selective Regulation of NR2B by Protein Phosphatase-1 for the Control of the NMDA Receptor in Neuroprotection

Cited by 20 publications

References 59 publications

Endogenous casein kinase‐1 modulates NMDA receptor activity of hypothalamic presympathetic neurons and sympathetic outflow in hypertension

Endogenous casein kinase‐1 modulates NMDA receptor activity of hypothalamic presympathetic neurons and sympathetic outflow in hypertension

Differential association of postsynaptic signaling protein complexes in striatum and hippocampus

α7nAChR‐mediated recruitment of PP1γ promotes TRAF6/NF‐κB cascade to facilitate the progression of Hepatocellular Carcinoma

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