ADP receptor P2Y13 induce apoptosis in pancreatic β-cells

Tan, Chanyuan; Salehi, Albert; Svensson, Sven; Olde, Björn; Erlinge, David

doi:10.1007/s00018-009-0191-3

Cited by 37 publications

(34 citation statements)

References 31 publications

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“…In a previous study, we showed that stimulation of purinergic P2Y 13 receptors on beta cells activates apoptotic pathways [6]. The aim of the present study was to determine if high glucose and free fatty acids contribute to beta cell apoptosis via autocrine/paracrine activation of the P2Y 13 receptor.…”

Section: Discussionmentioning

confidence: 98%

“…High glucose and palmitate stimulation of MIN6c4 cells causes autocrine activation of Caspase-3 through P2Y 13 We have previously reported that activation of the purinergic receptor P2Y 13 , on MIN6c4 cells, results in activation of proapoptotic pathways [6]. We next investigated if high glucose or palmitate could influence Caspase-3 level in MIN6c4 insulinoma cells cultured for 36 h and to what extent this effect could be inhibited by MRS2211.…”

Section: Atp Release Triggered By High Glucose or Palmitate Inhibits mentioning

confidence: 99%

“…In our previous studies, we demonstrated that extracellular ADP inhibits beta cell insulin secretion [5] and causes beta cell apoptosis by acting on P2Y 13 receptors [6]. The aim of the present study was to put this mechanism into a functional perspective, investigating if autocrine/paracrine activation of purinergic receptors might be involved in the proapoptotic effects of high glucose and FFA.…”

Section: Introductionmentioning

confidence: 99%

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High glucose and free fatty acids induce beta cell apoptosis via autocrine effects of ADP acting on the P2Y13 receptor

Tan

Voss

Svensson

et al. 2012

Purinergic Signalling

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While high levels of glucose and saturated fatty acids are known to have detrimental effects on beta cell function and survival, the signalling pathways mediating these effects are not entirely known. In a previous study, we found that ADP regulates beta cell insulin secretion and beta cell apoptosis. Using MIN6c4 cells as a model system, we investigated if autocrine/paracrine mechanisms of ADP and purinergic receptors are involved in this process. High glucose (16.7 mmol/l) and palmitate (100 μmol/l) rapidly and potently elevated the extracellular ATP levels, while mannitol was without effect. Both tolbutamide and diazoxide were without effect, while the calcium channel blocker nifedipine, the volume-regulated anion channels (VRAC) inhibitor NPPB, and the pannexin inhibitor carbenoxolone could inhibit both effects. Similarly, silencing the MDR1 gene also blocked nutrient-generated ATP release. These results indicate that calcium channels and VRAC might be involved in the ATP release mechanism. Furthermore, high glucose and palmitate inhibited cAMP production, reduced cell proliferation in MIN6c4 and increased activated Caspase-3 cells in mouse islets and in MIN6c4 cells. The P2Y 13 -specific antagonist MRS2211 antagonized all these effects. Further studies showed that blocking the P2Y 13 receptor resulted in enhanced CREB, Bad and IRS-1 phosphorylation, which are known to be involved in beta cell survival and insulin secretion. These findings provide further support for the concept that P2Y 13 plays an important role in beta cell apoptosis and suggest that autocrine/ paracrine mechanisms, related to ADP and P2Y 13 receptors, contribute to glucolipotoxicity.

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Section: Discussionmentioning

confidence: 98%

Section: Atp Release Triggered By High Glucose or Palmitate Inhibits mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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High glucose and free fatty acids induce beta cell apoptosis via autocrine effects of ADP acting on the P2Y13 receptor

Tan

Voss

Svensson

et al. 2012

Purinergic Signalling

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“…It was shown that P2Y 6 receptor agonists not only increase insulin secretion, but prevent b-cell death induced by tumour necrosis factor-a (Balasubramanian et al 2010). On the other hand, it seems that activation of the P2Y 13 receptor of the mouse pancreatic insulinoma cell line, MIN6C4, has a pronounced proapoptotic effect; 2-metylthio ADP reduced cell proliferation and increased caspase-3 activity, effects that were reversed by the P2Y 13 receptor antagonist, MRS2211 (Tan et al 2010). Extracellular ATP (1 mM) increased insulin secretion in mouse b-cell lines, probably via P2Y 1 and P2X 4 receptors, though at higher ATP concentrations in the medium, cell viability decreased (Ohtani et al 2011).…”

Section: Diabetes and Pancreasmentioning

confidence: 99%

Purinergic signalling in the pancreas in health and disease

Burnstock

Novak²

2012

Journal of Endocrinology

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Pancreatic cells contain specialised stores for ATP. Purinergic receptors (P2 and P1) and ecto-nucleotidases are expressed in both endocrine and exocrine calls, as well as in stromal cells. The pancreas, especially the endocrine cells, were an early target for the actions of ATP. After the historical perspective of purinergic signalling in the pancreas, the focus of this review will be the physiological functions of purinergic signalling in the regulation of both endocrine and exocrine pancreas. Next, we will consider possible interaction between purinergic signalling and other regulatory systems and their relation to nutrient homeostasis and cell survival. The pancreas is an organ exhibiting several serious diseases -cystic fibrosis, pancreatitis, pancreatic cancer and diabetes -and some are associated with changes in life-style and are increasing in incidence. There is upcoming evidence for the role of purinergic signalling in the pathophysiology of the pancreas, and the new challenge is to understand how it is integrated with other pathological processes.

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“…(23) In addition, it was recently shown that blocking the P2Y 13 receptor can mediate ERK1/2 involvement in b-cell apoptosis. (24) Interestingly, ERK1/2 signaling was demonstrated to be involved in osteoblastic response upon mechanical strain and fluid flow. (17,25) Given the expression of P2Y 13 receptor by osteoblasts and the observed negative feedback pathway for ATP release in red blood cells, we hypothesized that the P2Y 13 receptor would play a role in the osteogenic response to mechanical stimulation via regulating ATP metabolism in osteoblasts.…”

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confidence: 99%

The P2Y13 receptor regulates extracellular ATP metabolism and the osteogenic response to mechanical loading

Wang

Rumney

Yang

et al. 2013

Journal of Bone and Mineral Research

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ATP release and subsequent activation of purinergic receptors has been suggested to be one of the key transduction pathways activated by mechanical stimulation of bone. The P2Y 13 receptor, recently found to be expressed by osteoblasts, has been suggested to provide a negative feedback pathway for ATP release in different cell types. Therefore, we hypothesized that the P2Y 13 receptor may contribute to the mediation of osteogenic responses to mechanical stimulation by regulating ATP metabolism by osteoblasts. To test this hypothesis, wild-type (WT) and P2Y 13 receptor knockout (P2Y 13 R À/À ) mice were subject to non-invasive axial mechanical loading of the left tibiae to induce an osteogenic response. Micro-computed tomography analysis showed mechanical loading induced an osteogenic response in both strains of mice in terms of increased total bone volume and cortical bone volume, with the P2Y 13 R À/À mice having a significantly greater response. The extent of the increased osteogenic response was defined by dynamic histomorphometry data showing dramatically increased bone formation and mineral apposition rates in P2Y 13 R À/À mice compared with controls. In vitro, primary P2Y 13 R À/À osteoblasts had an accumulation of mechanically induced extracellular ATP and reduced levels of hydrolysis. In addition, P2Y 13 R À/À osteoblasts also had a reduction in their maximal alkaline phosphatase (ALP) activity, one of the main ecto-enzymes expressed by osteoblasts, which hydrolyzes extracellular ATP. In conclusion, deletion of the P2Y 13 receptor leads to an enhanced osteogenic response to mechanical loading in vivo, possibly because of the reduced extracellular ATP degradation by ALP. The augmented osteogenic response to mechanical stimulation, combined with suppressed bone remodeling activities and protection from OVXinduced bone loss after P2Y 13 receptor depletion as previously described, suggests a potential role for P2Y 13 receptor antagonist-based therapy, possibly in combination with mechanical loading, for the treatment of osteoporosis.

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ADP receptor P2Y13 induce apoptosis in pancreatic β-cells

Cited by 37 publications

References 31 publications

High glucose and free fatty acids induce beta cell apoptosis via autocrine effects of ADP acting on the P2Y13 receptor

High glucose and free fatty acids induce beta cell apoptosis via autocrine effects of ADP acting on the P2Y13 receptor

Purinergic signalling in the pancreas in health and disease

The P2Y13 receptor regulates extracellular ATP metabolism and the osteogenic response to mechanical loading

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