Evidence for the existence of pyrimidinergic transmission in rat brain

Cansev, Mehmet; Orhan, Fulya; Yaylagul, Esra Orenlili; Işık, Esra; Turkyilmaz, Mesut; Aydin, Sami; Gümüş, Abdullah; Sevinc, Cansu; Coşkun, Necdet; Ulus, İsmail H.; Wurtman, Richard J.

doi:10.1016/j.neuropharm.2014.12.019

Cited by 13 publications

(7 citation statements)

References 49 publications

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“…A recent study demonstrated the existence of uracil nucleotides, including UDP, in the brain extracellular fluid obtained from freely moving rats (Cansev et al 2015). The excitotoxicity of brain injury induced by kainic acid Fig.…”

Section: Discussionmentioning

confidence: 97%

Enhancement by Uridine Diphosphate of Macrophage Inflammatory Protein-1 Alpha Production in Microglia Derived from Sandhoff Disease Model Mice

et al. 2015

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Sandhoff disease (SD) is a lysosomal β-hexosaminidase (Hex) deficiency involving excessive accumulation of undegraded substrates, including GM2 ganglioside, and progressive neurodegeneration. Macrophage inflammatory protein-1α (MIP-1α) is a crucial factor for microglia-mediated neuroinflammation in the onset or progression of SD. However, the transmitter-mediated production of MIP-1α in SD is still poorly understood.Extracellular nucleotides, including uridine diphosphate (UDP), leaked by either injured or damaged neuronal cells activate microglia to trigger chemotaxis, phagocytosis, macropinocytosis, and cytokine production.In this study, we demonstrated that UDP enhanced the production of MIP-1α by microglia derived from SD mice (SD-Mg), but not that from wild-type mice (WT-Mg). The UDP-induced MIP-1α production was mediated by the activation of P2Y6 receptor, ERK, and JNK. We also found the amount of dimeric P2Y6 receptor protein to have increased in SD-Mg in comparison to WT-Mg. In addition, we demonstrated that the disruption of lipid rafts enhanced the effect of UDP on MIP-1α production and the disordered maintenance of the lipid rafts in SD-Mg. Thus, the accumulation of undegraded substrates might cause the enhanced effect of UDP in SD-Mg through the increased expression of the dimeric P2Y6 receptors and the disordered maintenance of the lipid rafts. These findings provide new insights into the pathogenic mechanism and therapeutic strategies for SD.

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Section: Discussionmentioning

confidence: 97%

Enhancement by Uridine Diphosphate of Macrophage Inflammatory Protein-1 Alpha Production in Microglia Derived from Sandhoff Disease Model Mice

et al. 2015

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“…To measure intracellular IP 3 levels, we used a HitHunter IP 3 Fluorescence Polarization Assay Kit from DiscoveRx (Fremont, CA) by following manufacturer’s instructions (Jin et al, 2013b; Tabatadze et al, 2015; Cansev et al, 2015). …”

Section: Methodsmentioning

confidence: 99%

The Role of Extracellular Signal-Regulated Kinases (ERK) in the Regulation of mGlu5 Receptors in Neurons

2018

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The metabotropic glutamate (mGlu) receptor 5 is a G protein-coupled receptor and is densely expressed in the mammalian brain. Like other glutamate receptors, mGlu5 receptors are tightly regulated by posttranslational modifications such as phosphorylation, although underlying mechanisms are incompletely investigated. In this study, we investigated the role of a prime kinase, extracellular signal-regulated kinase 1 (ERK1), in the phosphorylation and regulation of mGlu5 receptors in vitro and in striatal neurons. We found that recombinant ERK1 proteins directly bound to the C-terminal (CT) tail of mGlu5 receptors in vitro. Endogenous ERK1 also interacted with mGlu5 receptor proteins in adult rat striatal neurons in vivo. The kinase showed the ability to phosphorylate mGlu5 receptors. A serine residue in the distal region of mGlu5 CT was found to be a primary phosphorylation site sensitive to ERK1. In functional studies, we found that pharmacological inhibition of ERK with an inhibitor U0126 reduced the efficacy of mGlu5 receptors in stimulating production of cytoplasmic inositol-1,4,5-triphosphate, a major downstream conventional signaling event, in striatal neurons under normal conditions. These results identify mGlu5 as a new biochemical substrate of ERK1. The kinase can interact with and phosphorylate an intracellular domain of mGlu5 receptors in striatal neurons and thereby control its signaling efficacy.

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“…Intracellular IP 3 levels in rat cerebellar slices or HEK293T cells were measured using a HitHunter IP 3 Fluorescence Polarization Assay Kit from DiscoveRx or a rat IP3 ELISA kit from CUSABIO following the manufacturer instructions ( Jin et al, 2013 ; Cansev et al, 2015 ; Tabatadze et al, 2015 ).…”

Section: Methodsmentioning

confidence: 99%

An Essential Role of Fyn in the Modulation of Metabotropic Glutamate Receptor 1 in Neurons

Jin

Mao

Wang

2017

eNeuro

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Fyn is a member of the Src family of nonreceptor tyrosine kinases and is broadly expressed in the CNS. As a synapse-enriched kinase, Fyn interacts with and phosphorylates local substrates to regulate synaptic transmission and plasticity, although our knowledge of specific targets of Fyn at synaptic sites remains incomplete and the accurate role of Fyn in regulating synaptic proteins is poorly understood. In this study, we initiated an effort to explore the interaction of Fyn with a metabotropic glutamate receptor (mGluR). We found that recombinant Fyn directly binds to mGluR1a at a consensus binding motif located in the intracellular C-terminus (CT) of mGluR1a in vitro. Similarly, endogenous Fyn interacts with mGluR1a in adult rat cerebellar neurons in vivo. Active Fyn phosphorylates mGluR1a at a conserved tyrosine residue in the CT region. In cerebellar neurons and transfected HEK293T cells, the Fyn-mediated tyrosine phosphorylation of mGluR1a is constitutively active and acts to facilitate the surface expression of mGluR1a and to potentiate the mGluR1a postreceptor signaling. These results support mGluR1a to be a novel substrate of Fyn. Fyn, by binding to and phosphorylating mGluR1a, potentiates surface expression and signaling of the receptors.

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Evidence for the existence of pyrimidinergic transmission in rat brain

Cited by 13 publications

References 49 publications

Enhancement by Uridine Diphosphate of Macrophage Inflammatory Protein-1 Alpha Production in Microglia Derived from Sandhoff Disease Model Mice

Enhancement by Uridine Diphosphate of Macrophage Inflammatory Protein-1 Alpha Production in Microglia Derived from Sandhoff Disease Model Mice

The Role of Extracellular Signal-Regulated Kinases (ERK) in the Regulation of mGlu5 Receptors in Neurons

An Essential Role of Fyn in the Modulation of Metabotropic Glutamate Receptor 1 in Neurons

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