P2Y1 receptor mediated neuronal fibre outgrowth in organotypic brain slice co-cultures

Heine, Claudia; Sygnecka, Katja; Scherf, Nico; Grohmann, Marcus; Bräsigk, Annett; Franke, Heike

doi:10.1016/j.neuropharm.2015.02.001

Cited by 14 publications

(9 citation statements)

References 87 publications

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Section: Discussionsupporting

confidence: 87%

“…The TagRFP and thus P2RY1 gene expression within the olfactory bulb are in agreement with the known expression pattern of the P2Y 1 R in the olfactory bulb as assessed by functional analysis [43]. We found P2RY1 gene expression in dopaminergic neurons of the VTA, which fits well to functional data showing that stimulation of the P2Y 1 R expressed in the VTA resulted in the increased release of glutamate [44] and neuronal fiber growth [45]. Other transgenic models A BAC transgenic tool with which to study P2X4R-expressing cells is P2RX4 reporter mice Tg(P2RX4-tdTomato)1Khakh expressing the red fluorescent protein tdTomato under the control of the P2X4 locus by insertion into exon 1 of the P2RX4 gene to replace the endogenous initiation of translation codon in the BAC clone RP23-448O6 [46].…”

Section: Transgenic Mice As Tools To Analyze the P2r Expressionsupporting

confidence: 88%

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BAC transgenic mice to study the expression of P2X2 and P2Y1 receptors

Grohmann

Schumacher

Günther

et al. 2021

Purinergic Signalling

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Extracellular purines are important signaling molecules involved in numerous physiological and pathological processes via the activation of P2 receptors. Information about the spatial and temporal P2 receptor (P2R) expression and its regulation remains crucial for the understanding of the role of P2Rs in health and disease. To identify cells carrying P2X2Rs in situ, we have generated BAC transgenic mice that express the P2X2R subunits as fluorescent fusion protein (P2X2-TagRFP). In addition, we generated a BAC P2Y1R TagRFP reporter mouse expressing a TagRFP reporter for the P2RY1 gene expression. We demonstrate expression of the P2X2R in a subset of DRG neurons, the brain stem, the hippocampus, as well as on Purkinje neurons of the cerebellum. However, the weak fluorescence intensity in our P2X2R-TagRFP mouse precluded tracking of living cells. Our P2Y1R reporter mice confirmed the widespread expression of the P2RY1 gene in the CNS and indicate for the first time P2RY1 gene expression in mouse Purkinje cells, which so far has only been described in rats and humans. Our P2R transgenic models have advanced the understanding of purinergic transmission, but BAC transgenic models appeared not always to be straightforward and permanent reliable. We noticed a loss of fluorescence intensity, which depended on the number of progeny generations. These problems are discussed and may help to provide more successful animal models, even if in future more versatile and adaptable nuclease-mediated genome-editing techniques will be the methods of choice.

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Section: Discussionsupporting

confidence: 87%

Section: Transgenic Mice As Tools To Analyze the P2r Expressionsupporting

confidence: 88%

BAC transgenic mice to study the expression of P2X2 and P2Y1 receptors

Grohmann

Schumacher

Günther

et al. 2021

Purinergic Signalling

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“…The activation of P2Y receptors plays important roles in the nervous system. The activation of P2Y1 receptor can modulate neuronal activity and neuronal fiber outgrowth [ 10 , 11 ], and P2Y12 receptor is involved in microglial migration driven by ATP [ 12 ]. There is evidence of a prominent role of P2Y2 receptor in Alzheimer’s disease pathology [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Microglia P2Y6 receptor is related to Parkinson’s disease through neuroinflammatory process

Yang

Lou

Liu

et al. 2017

J Neuroinflammation

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BackgroundMicroglia in the central nervous system (CNS) were reported to play crucial role in neurodegeneration. Previous studies showed that P2Y6 receptor (P2Y6R) mainly contributed to microglia activation and phagocytosis in CNS. However, the level of P2Y6R in Parkinson’s disease (PD) patients is unclear. Therefore, we measured the level of P2Y6R in PD patients and speculated whether it could be a potential biomarker for PD. Given on the basis that P2Y6R was higher in PD patients, we further explored the mechanisms underlying P2Y6R in the pathogenesis of PD.MethodsWe tested the expression level of P2Y6R in the peripheral blood mononuclear cells (PBMCs) among 145 PD patients, 170 healthy controls, and 30 multiple system atrophy (MSA) patients. We also used a lipopolysaccharide (LPS)-stimulated microglial cell culture model to investigate (i) the effects of LPS on P2Y6R expression with western blot and RT-PCR, (ii) the effects of LPS on UDP expression using HPLC, (iii) the effects of UDP/P2Y6R signaling on cytokine expression using western blot, RT-PCR, and ELISA, and (iv) the signaling pathways activated by the P2Y6R involved in the neuroinflammation.ResultsExpression levels of P2Y6R in PD patients were higher than healthy controls and MSA patients. P2Y6R could be a good biomarker of PD. P2Y6R was also upregulated in LPS-treated BV-2 cells and involved in proinflammatory cytokine release through an autocrine loop based on LPS-triggered UDP secretion and accelerated neuroinflammatory responses through the ERK1/2 pathway. Importantly, blocking UDP/P2Y6R signaling could reverse these pathological processes.ConclusionsP2Y6R may be a potential clinical biomarker of PD. Blocking P2Y6R may be a potential therapeutic approach to the treatment of PD patients through inhibition of microglia-activated neuroinflammation.

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“…P2Y 1 R regulates regenerative responses in several tissues. P2Y 1 R mediates chondrocyte proliferation and cartilage repair in osteoarthritis 49 , neuronal fibre outgrowth in organotypic brain slice co-cultures 50 , expression of wound healing regulator cyclooxygenase-2 in intestinal subepithelial myofibroblasts 51 in addition to regulating proliferation and repair of retinal tissue in response to cytotoxic injury 52 . The UDP-sugar P2Y 14 receptor (P2Y 14 R) is another interesting target downregulated in S-hCPCs compared to fast-growing cells (Figure 2H).…”

Section: Discussionmentioning

confidence: 99%

P2Y ₂ Nucleotide Receptor Prompts Human Cardiac Progenitor Cell Activation by Modulating Hippo Signaling

et al. 2017

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Rationale Autologous stem cell therapy using human c-Kit+ cardiac progenitor cells (hCPCs) is a promising therapeutic approach for treatment of heart failure (HF). However, hCPCs derived from aged HF patients with genetic predispositions and/or comorbidities of chronic diseases exhibit poor proliferative and migratory capabilities, which impairs overall reparative potential for injured myocardium. Therefore, empowering functionally compromised hCPCs with pro-regenerative molecules ex vivo is crucial for improving the therapeutic outcome in HF patients. Objective To improve hCPC proliferation and migration responses that are critical for regeneration by targeting pro-regenerative P2Y2 nucleotide receptor (P2Y2R) activated by extracellular ATP and UTP molecules released following injury/stress. Methods and Results c-Kit+ hCPCs were isolated from cardiac tissue of HF patients undergoing left ventricular assist device (LVAD) implantation surgery. Correlations between P2 nucleotide receptor expression and hCPC growth kinetics revealed downregulation of select P2 receptors, including P2Y2R, in slow-growing hCPCs compared to fast-growers. hCPC proliferation and migration significantly improved by overexpressing or stimulating P2Y2R. Mechanistically, P2Y2R-induced proliferation and migration were dependent upon activation of yes-associated protein (YAP), the downstream effector of Hippo signaling pathway. Conclusions Proliferation and migration of functionally impaired hCPCs are enhanced by P2Y2R-mediated YAP activation, revealing a novel link between extracellular nucleotides released during injury/stress and Hippo signaling, a central regulator of cardiac regeneration. Functional correlations exist between hCPC phenotypic properties and P2 purinergic receptor expression. Lack of P2Y2R and other crucial purinergic stress detectors could compromise hCPC responsiveness to presence of extracellular stress signals. These findings set the stage for subsequent studies to assess purinergic signaling modulation as a potential strategy to improve therapeutic outcome for use of hCPCs in HF patients.

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P2Y1 receptor mediated neuronal fibre outgrowth in organotypic brain slice co-cultures

Cited by 14 publications

References 87 publications

BAC transgenic mice to study the expression of P2X2 and P2Y1 receptors

BAC transgenic mice to study the expression of P2X2 and P2Y1 receptors

Microglia P2Y6 receptor is related to Parkinson’s disease through neuroinflammatory process

P2Y ₂ Nucleotide Receptor Prompts Human Cardiac Progenitor Cell Activation by Modulating Hippo Signaling

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P2Y1 receptor mediated neuronal fibre outgrowth in organotypic brain slice co-cultures

Cited by 14 publications

References 87 publications

BAC transgenic mice to study the expression of P2X2 and P2Y1 receptors

BAC transgenic mice to study the expression of P2X2 and P2Y1 receptors

Microglia P2Y6 receptor is related to Parkinson’s disease through neuroinflammatory process

P2Y 2 Nucleotide Receptor Prompts Human Cardiac Progenitor Cell Activation by Modulating Hippo Signaling

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P2Y ₂ Nucleotide Receptor Prompts Human Cardiac Progenitor Cell Activation by Modulating Hippo Signaling