Uridine diphosphate (UDP) stimulates insulin secretion by activation of P2Y6 receptors

Parandeh, Fariborz; Abaraviciene, Sandra Meidute; Amisten, Stefan; Erlinge, David; Salehi, Albert

doi:10.1016/j.bbrc.2008.03.119

Cited by 41 publications

(46 citation statements)

References 27 publications

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“…mRNA quantification is therefore a useful complement to investigate the importance of the many subtypes. In mouse beta cells and also in whole islets we found a very clear and consistent pattern, with high expression levels of P2Y 1 and P2Y 13 receptors, but extremely low or undetectable levels of P2Y 2 , P2Y 4 [38] or P2Y 12 receptors (P2Y 11 is absent from the mouse genome). Therefore, we conclude that no pharmacologically relevant P2Y receptors for ATP are present in mouse beta cells or islets.…”

Section: Discussionsupporting

confidence: 66%

ADP mediates inhibition of insulin secretion by activation of P2Y13 receptors in mice

et al. 2010

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Aims/hypotheses To investigate the effects of extracellular purines on insulin secretion from mouse pancreatic islets. Methods Mouse islets and beta cells were isolated and examined with mRNA real-time quantification, cAMP quantification and insulin and glucagon secretion. ATP release was measured in MIN6c4 cells. Insulin and glucagon secretion were measured in vivo after glucose injection. Results Enzymatic removal of extracellular ATP at low glucose levels increased the secretion of both insulin and glucagon, while at high glucose levels insulin secretion was reduced and glucagon secretion was stimulated, indicating an autocrine effect of purines. In MIN6c4 cells it was shown that glucose does induce release of ATP into the extracellular space. Quantitative real-time PCR demonstrated the expression of the ADP receptors P2Y 1 and P2Y 13 in both intact mouse pancreatic islets and isolated beta cells. The stable ADP analogue 2-MeSADP had no effect on insulin secretion. However, co-incubation with the P2Y 1 antagonist MRS2179 inhibited insulin secretion, while coincubation with the P2Y 13 antagonist MRS2211 stimulated insulin secretion, indicating that ADP acting via P2Y 1 stimulates insulin secretion, while signalling via P2Y 13 inhibits the secretion of insulin. P2Y 13 antagonism through MRS2211 per se increased the secretion of both insulin and glucagon at intermediate (8.3 mmol/l) and high (20 mmol/l) glucose levels, confirming an autocrine role for ADP. Administration of MRS2211 during glucose injection in vivo resulted in both increased secretion of insulin and reduced glucose levels. Conclusions/interpretation In conclusion, ADP acting on the P2Y 13 receptors inhibits insulin release. An antagonist to P2Y 13 increases insulin release and could be evaluated for the treatment of diabetes.

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Section: Discussionsupporting

confidence: 66%

ADP mediates inhibition of insulin secretion by activation of P2Y13 receptors in mice

et al. 2010

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“…To do so, and also to identify the GPCR subtypes involved in this feedback loop, we studied glucose-induced insulin secretion in isolated islets in the absence and presence of different GPCR antagonists ( Figure 5F). Since murine β cells have been shown to express the UDP receptor P2Y 6 as well as the ADP/ATP receptor P2Y 1 (19,27), we used the P2Y 1 receptor antagonist MRS2179 and the P2Y 6 antagonist MRS2578 for this purpose. In vehicletreated control islets, elevation of glucose concentration from 2.8 mM to 16.7 mM resulted in a significant increase in insulin secretion.…”

Section: Figurementioning

confidence: 99%

“…The two main members of the G q /G 11 family, G q and G 11 , are ubiquitously expressed (16,17); their activation results in stimulation of phospholipase C β (PLC β) isoforms and consequent inositol 1,4,5-trisphosphate-mediated (IP 3 -mediated) intracellular calcium mobilization and PKC activation (18). Interestingly, β cells express in addition to M 3 a wide variety of other potentially G q /G 11 -coupled receptors (19)(20)(21), and most of these receptors have been shown to be involved in the potentiation of insulin secretion, such as receptors for fatty acids (22), cholecystokinin (23), arginine vasopressin (24,25), endothelin (26), extracellular nucleotides (27,28), calcium (29), or zinc (30). Though for many of these receptors, the physiological relevance in the regulation of insulin secretion is unclear, the sheer number of potentially G q /G 11 -coupled receptors expressed in β cells suggests an important role of this G protein family in regulation of β cell function.…”

Section: Introductionmentioning

confidence: 99%

The Gq/G11-mediated signaling pathway is critical for autocrine potentiation of insulin secretion in mice

Sassmann¹,

Gier²,

Gröne³

et al. 2010

J. Clin. Invest.

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A variety of neurotransmitters, gastrointestinal hormones, and metabolic signals are known to potentiate insulin secretion through GPCRs. We show here that β cell-specific inactivation of the genes encoding the G protein α-subunits Gα q and Gα 11 resulted in impaired glucose tolerance and insulin secretion in mice. Interestingly, the defects observed in Gα q /Gα 11 -deficient β cells were not restricted to loss of muscarinic or metabolic potentiation of insulin release; the response to glucose per se was also diminished. Electrophysiological recordings revealed that glucose-induced depolarization of isolated β cells was impaired in the absence of Gα q /Gα 11 , and closure of K ATP channels was inhibited. We provide evidence that this reduced excitability was due to a loss of β cell-autonomous potentiation of insulin secretion through factors cosecreted with insulin. We identified as autocrine mediators involved in this process extracellular nucleotides such as uridine diphosphate acting through the G q /G 11 -coupled P2Y6 receptor and extracellular calcium acting through the calciumsensing receptor. Thus, the G q /G 11 -mediated signaling pathway potentiates insulin secretion in response to glucose by integrating systemic as well as autocrine/paracrine mediators. IntroductionThe adequate secretion of insulin from pancreatic β cells is essential for the maintenance of normoglycemia; impaired insulin secretion results in diabetes mellitus with hyperglycemia, dyslipidemia, and consequent long-term tissue damage (1). The on-demand release of insulin from β cells is mainly regulated by blood glucose levels: high concentrations of glucose result in enhanced intracellular glucose metabolism with accumulation of ATP and consecutive closure of ATP-sensitive K + channels, leading to the opening of voltage-operated Ca 2+ channels and Ca 2+ -mediated exocytosis of insulin-containing vesicles (2, 3).While the ATP-dependent mechanism is clearly the master regulator of insulin release, various mediators potentiate insulin release in response to glucose. For example, gastrointestinal hormones such as glucose-dependent insulinotropic polypeptide (GIP) or glucagon-like peptide-1 (GLP-1) potentiate insulin secretion by activation of GPCRs, which signal through the G s family of heterotrimeric G proteins (4-6). The potentiating effect of G s on glucose-induced insulin release depends on activation of adenylyl cyclase and consecutive phosphorylation of voltage-operated Ca 2+ channels (7, 8) or opening of nonselective cation channels (9).Another important group of modulators are neurotransmitters and neuropeptides (10, 11), most prominent among them being the neurotransmitter acetylcholine, which is released from vagal nerve terminals and potentiates insulin secretion through the muscarinic receptor subtype M 3 (12)(13)(14)(15). In contrast to the receptors for GIP and GLP-1, the M 3 receptor does not elicit G smediated adenylyl cyclase activation, but was shown to signal through the G q /G 11 family of heterotrimeric G proteins. Th...

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“…P2Y 1 and P2Y 6 receptors in mouse β-cells mediated inhibition of insulin secretion at high glucose concentrations, but were slightly stimulant at 5 mM glucose [390]. Other studies showed clear stimulation of insulin secretion via these receptors at glucose concentrations >8 mM [17,405]. A further two receptors were identified, P2Y 11 and P2Y 12 , in human pancreatic islets and their involvement in stimulation of insulin secretion was postulated [333].…”

Section: β-Cellsmentioning

confidence: 99%

“…Studies on mice α-cells showed that they expressed P2 receptors. P2Y 6 receptors, activated by uridine 5′-O-thiodiphosphate, increased glucagon release [405]. In contrast, P2Y 1 receptors mediated inhibition of Ca 2+ signalling and glucagon secretion in mice α-cells [554].…”

Section: α-Cellsmentioning

confidence: 99%

Purinergic signalling in endocrine organs

Burnstock

2013

Purinergic Signalling

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There is widespread involvement of purinergic signalling in endocrine biology. Pituitary cells express P1, P2X and P2Y receptor subtypes to mediate hormone release. Adenosine 5′-triphosphate (ATP) regulates insulin release in the pancreas and is involved in the secretion of thyroid hormones. ATP plays a major role in the synthesis, storage and release of catecholamines from the adrenal gland. In the ovary purinoceptors mediate gonadotrophin-induced progesterone secretion, while in the testes, both Sertoli and Leydig cells express purinoceptors that mediate secretion of oestradiol and testosterone, respectively. ATP released as a cotransmitter with noradrenaline is involved in activities of the pineal gland and in the neuroendocrine control of the thymus. In the hypothalamus, ATP and adenosine stimulate or modulate the release of luteinising hormone-releasing hormone, as well as arginine-vasopressin and oxytocin. Functionally active P2X and P2Y receptors have been identified on human placental syncytiotrophoblast cells and on neuroendocrine cells in the lung, skin, prostate and intestine. Adipocytes have been recognised recently to have endocrine function involving purinoceptors.

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Uridine diphosphate (UDP) stimulates insulin secretion by activation of P2Y6 receptors

Cited by 41 publications

References 27 publications

ADP mediates inhibition of insulin secretion by activation of P2Y13 receptors in mice

ADP mediates inhibition of insulin secretion by activation of P2Y13 receptors in mice

The Gq/G11-mediated signaling pathway is critical for autocrine potentiation of insulin secretion in mice

Purinergic signalling in endocrine organs

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