Nucleotide P2Y13-stimulated phosphorylation of CREB is required for ADP-induced proliferation of late developing retinal glial progenitors in culture

Jacques, Flavia Jesus; Silva, Thayane Martins; Silva, Flavia Emenegilda da; Ornelas, Isis M.; Ventura, Ana Lúcia Marques

doi:10.1016/j.cellsig.2017.03.019

Cited by 15 publications

(12 citation statements)

References 56 publications

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“…They trigger several intracellular pathways related to the activation of MAPKs (mitogen-activated protein kinases) and the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3 axis (reviewed in Pérez-Sen et al, 2017 ). Pathways include inhibition of adenylyl cyclase and stimulation of Erk1/2 (Communi et al, 2001 ) and CREB phosphorylation (Jacques et al, 2017 ), elevation of intracellular Ca 2+ (Lyubchenko et al, 2011 ; Jacques et al, 2017 ), activation of the Nrf2/HO-1 (nuclear factor E2-related factor 2/hemoxigenase-1) axis protecting against oxidative stress-induced cell death (Espada et al, 2010 ), activation of RhoA and ROCK (Malaval et al, 2009 ), ROCK-dependent P38 MAK kinase (Tatsumi et al, 2015 ), or the ROCK/P38MAKP/NF-kb signaling pathway (Liu et al, 2017 ). In the pancreatic insulinoma-cell line MIN6c4, however, inhibition rather than activation of the P2Y 13 R enhanced ERK1/2, Akt and CREB phosphorylation, as well as cell proliferation (Tan et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Disruption of the Microglial ADP Receptor P2Y13 Enhances Adult Hippocampal Neurogenesis

Stefani

Tschesnokowa

Parrilla

et al. 2018

Front. Cell. Neurosci.

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In mammalian species, including humans, the hippocampal dentate gyrus (DG) is a primary region of adult neurogenesis. Aberrant adult hippocampal neurogenesis is associated with neurological pathologies. Understanding the cellular mechanisms controlling adult hippocampal neurogenesis is expected to open new therapeutic strategies for mental disorders. Microglia is intimately associated with neural progenitor cells in the hippocampal DG and has been implicated, under varying experimental conditions, in the control of the proliferation, differentiation and survival of neural precursor cells. But the underlying mechanisms remain poorly defined. Using fluorescent in situ hybridization we show that microglia in brain express the ADP-activated P2Y13 receptor under basal conditions and that P2ry13 mRNA is absent from neurons, astrocytes, and neural progenitor cells. Disrupting P2ry13 decreases structural complexity of microglia in the hippocampal subgranular zone (SGZ). But it increases progenitor cell proliferation and new neuron formation. Our data suggest that P2Y13 receptor-activated microglia constitutively attenuate hippocampal neurogenesis. This identifies a signaling pathway whereby microglia, via a nucleotide-mediated mechanism, contribute to the homeostatic control of adult hippocampal neurogenesis. Selective P2Y13R antagonists could boost neurogenesis in pathological conditions associated with impaired hippocampal neurogenesis.

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Section: Discussionmentioning

confidence: 99%

Disruption of the Microglial ADP Receptor P2Y13 Enhances Adult Hippocampal Neurogenesis

Stefani

Tschesnokowa

Parrilla

et al. 2018

Front. Cell. Neurosci.

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“…The activation of P2Y13 receptor by ADP triggers the cAMP/PKA pathways in retinal glial progenitors in the cell culture [96]. This P2Y13 pathway has not been reported in α-cells.…”

Section: Atp Contributes To Insulin Resistance Through Hyperglucagonemiamentioning

confidence: 78%

Mechanism of insulin resistance in obesity: a role of ATP

2021

Front. Med.

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Obesity increases the risk of type 2 diabetes through the induction of insulin resistance. The mechanism of insulin resistance has been extensively investigated for more than 60 years, but the essential pathogenic signal remains missing. Existing hypotheses include inflammation, mitochondrial dysfunction, hyperinsulinemia, hyperglucagonemia, glucotoxicity, and lipotoxicity. Drug discoveries based on these hypotheses are unsuccessful in the development of new medicines. In this review, multidisciplinary literature is integrated to evaluate ATP as a primary signal for insulin resistance. The ATP production is elevated in insulin-sensitive cells under obese conditions independent of energy demand, which we have named “mitochondrial overheating.” Overheating occurs because of substrate oversupply to mitochondria, leading to extra ATP production. The ATP overproduction contributes to the systemic insulin resistance through several mechanisms, such as inhibition of AMPK, induction of mTOR, hyperinsulinemia, hyperglucagonemia, and mitochondrial dysfunction. Insulin resistance represents a feedback regulation of energy oversupply in cells to control mitochondrial overloading by substrates. Insulin resistance cuts down the substrate uptake to attenuate mitochondrial overloading. The downregulation of the mitochondrial overloading by medicines, bypass surgeries, calorie restriction, and physical exercise leads to insulin sensitization in patients. Therefore, ATP may represent the primary signal of insulin resistance in the cellular protective response to the substrate oversupply. The prevention of ATP overproduction represents a key strategy for insulin sensitization.

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“…According to the receptor activity identified in other tissues, ADP might generate two different effects on the cAMP/PKA/CREB pathway through an interaction with the P2Y13 receptor. At the mmol/L level, ADP activates the pathway (23,24). At the nanomolar level, ADP suppresses the pathway (23).…”

Section: Discussionmentioning

confidence: 99%

ADP Induces Blood Glucose Through Direct and Indirect Mechanisms in Promotion of Hepatic Gluconeogenesis by Elevation of NADH

Cao

Zhang

et al. 2021

Front. Endocrinol.

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Extracellular ADP, a derivative of ATP, interacts with the purinergic receptors in the cell membrane to regulate cellular activities. This signaling pathway remains unknown in the regulation of blood glucose in vivo. We investigated the acute activity of ADP in mice through a peritoneal injection. In the lean mice, in response to the ADP treatment, the blood glucose was elevated, and pyruvate tolerance was impaired. Hepatic gluconeogenesis was enhanced with elevated expression of glucogenic genes (G6pase and Pck1) in the liver. An elevation was observed in NADH, cAMP, AMP, GMP and citrate in the liver tissue in the targeted metabolomics assay. In the primary hepatocytes, ADP activated the cAMP/PKA/CREB signaling pathway, which was blocked by the antagonist (2211) of the ADP receptor P2Y13. In the circulation, gluconeogenic hormones including glucagon and corticosterone were elevated by ADP. Insulin and thyroid hormones (T3 and T4) were not altered in the blood. In the diet-induced obese (DIO) mice, NADH was elevated in the liver tissue to match the hepatic insulin resistance. Insulin resistance was intensified by ADP for further impairment in insulin tolerance. These data suggest that ADP induced the blood glucose through direct and indirect actions in liver. One of the potential pathways involves activation of the P2Y13/cAMP/PKA/CREB signaling pathway in hepatocytes and the indirect pathway may involve induction of the gluconeogenic hormones. NADH is a signal for gluconeogenesis in the liver of both DIO mice and lean mice.

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Nucleotide P2Y13-stimulated phosphorylation of CREB is required for ADP-induced proliferation of late developing retinal glial progenitors in culture

Cited by 15 publications

References 56 publications

Disruption of the Microglial ADP Receptor P2Y13 Enhances Adult Hippocampal Neurogenesis

Disruption of the Microglial ADP Receptor P2Y13 Enhances Adult Hippocampal Neurogenesis

Mechanism of insulin resistance in obesity: a role of ATP

ADP Induces Blood Glucose Through Direct and Indirect Mechanisms in Promotion of Hepatic Gluconeogenesis by Elevation of NADH

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