Functional characterization of the adenosine receptor contributing to glycogenolysis and gluconeogenesis in rat hepatocytes

Yasuda, Nobuyuki; Inoue, Takashi; Horizoe, Tatsuo; Nagata, Kaya; Minami, Hiroe; Kawata, Tsutomu; Hoshino, Yorihisa; Hishida, Hitoshi; Yoshikawa, Seiji; Asano, Osamu; Nagaoka, Junsaku; Murakami, Manabu; Abe, Shinya; Kobayashi, Seiichi; Tanaka, Isao

doi:10.1016/s0014-2999(02)02832-7

Cited by 60 publications

(48 citation statements)

References 30 publications

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“…As described under Results, incubation of freshly isolated cells with 2-MeSADP led to accumulation of 2-methylthio-substituted derivatives of adenosine and AMP. These compounds could activate adenosine A 2B receptors present on rat hepatocytes that are coupled to increased cyclic AMP levels (Yasuda et al, 2003). This could conceivably stimulate glycogen phosphorylase further through the classical pathway via protein kinase A activation.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of Rat Hepatocyte Function by P2Y Receptors: Focus on Control of Glycogen Phosphorylase and Cyclic AMP by 2-Methylthioadenosine 5′-Diphosphate

Dixon

Hall²,

Webb³

et al. 2004

J Pharmacol Exp Ther

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Hepatocyte function is regulated by several P2Y receptor subtypes. Here we report that 2-methylthioadenosine 5Ј-diphosphate (2-MeSADP), an agonist at P2Y 1 , P2Y 12 , and P2Y 13 receptors, potently (threshold 30 nM) stimulates glycogen phosphorylase in freshly isolated rat hepatocytes. Antagonism by N 6 -methyl 2Ј-deoxyadenosine 3Ј,5Ј-bisphosphate (MRS 2179) confirms that this response is mediated by P2Y 1 receptors. In addition, in these cells, both 2-MeSADP and UTP inhibited glucagon-stimulated cyclic AMP accumulation. This inhibitory effect of 2-MeSADP was not reversed by the P2Y 1 antagonists, adenosine-3Ј-phosphate-5Ј-phosphate (A3P5P) or MRS 2179, both in the range 1 to 300 M, indicating that it was not mediated by P2Y 1 receptors. This contrasts with the increase in cytosolic free Ca 2ϩ concentration ([Ca 2ϩ ] c ) induced by 2-MeSADP, which has shown to be inhibited by A3P5P. Pertussis toxin abolished the inhibitory effect of both UTP and 2-MeSADP. After culture of cells for 48 h, the ability of 2-Me-SADP to inhibit cyclic AMP accumulation was greatly diminished. Reverse transcriptase-polymerase chain reaction analysis revealed that during this culture period, there was a decline in the ability to detect transcripts for P2Y 12 and P2Y 13 receptors, both of which are activated by 2-MeSADP and negatively coupled to adenylyl cyclase. However, in freshly isolated cells, the P2Y 12 and P2Y 13 receptor antagonist, 2-propylthio-␤,␥-dichloromethylene-D-ATP (AR-C67085) (10 nM to 300 M) did not alter the ability of 2-MeSADP to inhibit glucagon-stimulated cyclic AMP accumulation. We conclude that 2-MeSADP regulates rat hepatocyte glycogen phosphorylase by acting on P2Y 1 receptors coupled to raised [Ca 2ϩ ] c , and by inhibiting cyclic AMP levels by an unknown G i -coupled receptor subtype, distinct from P2Y 1 , P2Y 12 , or P2Y 13 receptors.Glycogen phosphorylase, the rate-controlling enzyme in hepatic glycogenolysis, is activated by increases in both cyclic AMP and cytosolic free Ca 2ϩ concentration ([Ca 2ϩ ] c ), resulting in a net output of glucose to supply extrahepatic tissues, crucially the brain, when blood glucose levels drop. Extracellular nucleotides play a well established role in the regulation of this key function in rat hepatocytes through the activation of P2Y receptors (Okajima et al., 1987;Keppens et al., 1992Keppens et al., , 1993Keppens, 1993), a family of G-protein-coupled receptors responding to the native nucleotides ADP, ATP, UDP, UTP, and UDP-glucose (Boarder and Hourani, 1998;Abbracchio et al., 2003). Curiously, stimulation of P2Y receptors on rat hepatocytes leads to both increases in [Ca 2ϩ ] c and inhibition of adenylyl cyclase; these responses will stimulate and limit, respectively, activation of glycogen phosphorylase (Okajima et al., 1987;Dixon et al., 1990Dixon et al., , 1995Dixon et al., , 2000Keppens et al., 1992;1993;Keppens, 1993;Edgecombe et al., 1999). The mechanism underlying the regulation of glycogen phosphorylase by cyclic AMP is well established, with ...

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Section: Discussionmentioning

confidence: 99%

“…The P1 receptor present on these cells has been characterized as an A 2B receptor coupled to increases in cyclic AMP (Yasuda et al, 2003). Stimulation of this receptor would therefore counteract the inhibitory effect of 2-MeSADP on cyclic AMP generation.…”

Section: Activation Of Glycogen Phosphorylase By 2-mesadp In Freshly mentioning

confidence: 99%

Regulation of Rat Hepatocyte Function by P2Y Receptors: Focus on Control of Glycogen Phosphorylase and Cyclic AMP by 2-Methylthioadenosine 5′-Diphosphate

Dixon

Hall²,

Webb³

et al. 2004

J Pharmacol Exp Ther

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“…Evidence for adenosine A 2 subtype receptors on Kupffer cells was presented [209]. It was claimed that adenosine stimulates cyclic adenosine monophosphate (cAMP) formation and regulation of glycogenolysis and gluconeogenesis most likely through the A 2B receptor subtype in rat hepatocytes [265]. Adenosine A 2A receptor occupancy stimulates collagen expression by hepatic stellate cells (HSC; [45]).…”

Section: Receptor Subtypes For Purines and Pyrimidines On Hepatocytesmentioning

confidence: 99%

Purinergic signalling in the liver in health and disease

Burnstock

Vaughn

Robson

2013

Purinergic Signalling

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Purinergic signalling is involved in both the physiology and pathophysiology of the liver. Hepatocytes, Kupffer cells, vascular endothelial cells and smooth muscle cells, stellate cells and cholangiocytes all express purinoceptor subtypes activated by adenosine, adenosine 5′-triphosphate, adenosine diphosphate, uridine 5′-triphosphate or UDP. Purinoceptors mediate bile secretion, glycogen and lipid metabolism and indirectly release of insulin. Mechanical stress results in release of ATP from hepatocytes and Kupffer cells and ATP is also released as a cotransmitter with noradrenaline from sympathetic nerves supplying the liver. Ectonucleotidases play important roles in the signalling process. Changes in purinergic signalling occur in vascular injury, inflammation, insulin resistance, hepatic fibrosis, cirrhosis, diabetes, hepatitis, liver regeneration following injury or transplantation and cancer. Purinergic therapeutic strategies for the treatment of these pathologies are being explored.

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“…In skeletal muscle caffeine can increase the expression of Glucose Transporter type 4 (GLUT4) by increasing intracellular Ca 2+ concentration and AMPK expression 7,8 . Caffeine also antagonizes the adenosine receptors involved in glycogenolysis and gluconeogenesis found in the cell membranes of hepatocytes 9 .…”

mentioning

confidence: 99%

Ingestão aguda de cafeína reduz a glicemia sanguínea antes e após o exercício físico agudo em ratos diabéticos

et al. 2014

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A B S T R A C T ObjectiveThe present study investigated the effects of caffeine supplementation combined with acute physical exercise on the glycemic response of diabetic rats. MethodsThirty-two 60-day-old rats with a mean weight of 238±3 g were divided into four groups: control, control caffeine, diabetes, and diabetes/caffeine. Diabetes was induced by 60 mg/kg of streptozotocin intraperitoneally. The control groups received an acute dose of caffeine (6 mg) or saline 60 minutes before exercise. The animals were then forced to swim for 60 minutes carrying a ballast weighing 6% of their body weight, producing lactacidemia compatible with the maximum lactate production during the steady state (5.5 mmol/L). After the acute exercise session, the animals were sacrificed and their blood collected for glucose analysis. The cardiovascular responses were measured before and after supplementation by tail cuff plethysmography. The one-way AnalysisNutri1.pmd 27/5/2014, 08:33 143

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Functional characterization of the adenosine receptor contributing to glycogenolysis and gluconeogenesis in rat hepatocytes

Cited by 60 publications

References 30 publications

Regulation of Rat Hepatocyte Function by P2Y Receptors: Focus on Control of Glycogen Phosphorylase and Cyclic AMP by 2-Methylthioadenosine 5′-Diphosphate

Regulation of Rat Hepatocyte Function by P2Y Receptors: Focus on Control of Glycogen Phosphorylase and Cyclic AMP by 2-Methylthioadenosine 5′-Diphosphate

Purinergic signalling in the liver in health and disease

Ingestão aguda de cafeína reduz a glicemia sanguínea antes e após o exercício físico agudo em ratos diabéticos

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