Adenosine, an endogenous distress signal, modulates tissue damage and repair

Fredholm, Bertil B.

doi:10.1038/sj.cdd.4402132

Cited by 629 publications

(601 citation statements)

References 79 publications

Supporting

Mentioning

577

Contrasting

Unclassified

Order By: Relevance

“…However, the mRNA levels of A 1 and A 2A are about 100-fold higher than those of A 2B R and A 3 R (51), and the affinity of adenosine to A 1 R and A 2A R is at least as high as to A 2B and A 3 Rs (17). Since the potency of adenosine as an agonist depends on the density and affinity of the receptors (16,17), the possibility exists that intracardiac A 1 R and A 2A R could regulate HR. However, indirect effects are also possible.…”

Section: Discussionmentioning

confidence: 99%

“…It is much more potent on three of the known receptors, A 1 , A 2A , and A 2B (A 1 R, A 2A R, and A 2B R, respectively) than on the fourth, the A 3 R (17). Since a competitive antagonist will have effects only when and where receptors are activated by an agonist, it is relevant that endogenous agonist adenosine is more potent on A 1 R and A 2A R than on A 2B R. The potency of adenosine as an agonist in addition depends on the density of the receptors (16). The levels of adenosine are low under physiological condition but are sufficient to partially activate A 1 R, A 2A R, and A 3 Rs where the receptors are abundantly expressed.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Physiological roles of A₁ and A_2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine

Yang

Chen²,

Fredholm³

2009

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Yang JN, Chen JF, Fredholm BB. Physiological roles of A1 and A2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine. Am J Physiol Heart Circ Physiol 296: H1141-H1149, 2009. First published February 13, 2009 doi:10.1152/ajpheart.00754.2008.-Heart rate (HR), body temperature (Temp), locomotor activity (LA), and oxygen consumption (O2C) were studied in awake mice lacking one or both of the adenosine A 1 or A2A receptors (A1R or A2AR, respectively) using telemetry and respirometry, before and after caffeine administration. All parameters were lower during day than night and higher in females than males. When compared with wild-type (WT) littermates, HR was higher in male A 1R knockout (A1RKO) mice but lower in A2ARKO mice and intermediate in A1-A2AR double KO mice. A single dose of an unselective ␤-blocker (timolol; 1 mg/kg) abolished the HR differences between these genotypes. Deletion of A 1Rs had little effect on Temp, whereas deletion of A 2ARs increased it in females and decreased it in males. A 1-A2ARKO mice had lower Temp than WT mice. LA was unaltered in A 1RKO mice and lower in A 2ARKO and A1-A2ARKO mice than in WT mice. Caffeine injection increased LA but only in mice expressing A 2AR. Caffeine ingestion also increased LA in an A 2AR-dependent manner in male mice. Caffeine ingestion significantly increased O 2C in WT mice, but less in the different KO mice. Injection of 30 mg/kg caffeine decreased Temp, especially in KO mice, and hence in a manner unrelated to A 1R or A 2AR blockade. Selective A2B antagonism had little or no effect. Thus A 1R and A2AR influence HR, Temp, LA, and O2C in mice in a sex-dependent manner, indicating effects of endogenous adenosine. The A2AR plays an important role in the modulation of O2C and LA by acute and chronic caffeine administration. There is also evidence for effects of higher doses of caffeine being independent of both A 1R and A2AR. diurnal rhythm; metabolic rate; locomotor activity; adenosine; telemetry CAFFEINE (1,3,7-trimethylxanthine), the most widely consumed stimulant in the world, acts as a competitive antagonist of adenosine receptors (ARs) (18). It is much more potent on three of the known receptors, A 1 , A 2A , and A 2B (A 1 R, A 2A R, and A 2B R, respectively) than on the fourth, the A 3 R (17). Since a competitive antagonist will have effects only when and where receptors are activated by an agonist, it is relevant that endogenous agonist adenosine is more potent on A 1 R and A 2A R than on A 2B R. The potency of adenosine as an agonist in addition depends on the density of the receptors (16). The levels of adenosine are low under physiological condition but are sufficient to partially activate A 1 R, A 2A R, and A 3 Rs where the receptors are abundantly expressed. For these reasons caffeine is generally believed to act on A 1 R and A 2A R to exert most of its effects, at least when given in lower doses (18). However, a recent study showed that A 2B R knockout (A 2B RKO) mice have e...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Physiological roles of A₁ and A_2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine

Yang

Chen²,

Fredholm³

2009

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…Furthermore, ATP is rapidly degraded by ectonucleotidases to ADP [7], which can act on P2Y 1 , P2Y 12 and P2Y 13 receptors. ADP is then further degraded by ecto-5′-nucleotidase to adenosine, which in turn can activate four different adenosine receptors [8].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

View full text Add to dashboard Cite

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.

show abstract

“…Human aortic endothelial cells (HAECs) express the A 2b receptor (Iwamoto et al, 1994), and we confirmed A 2b expression by RT-PCR (not depicted). We treated HAECs with BAY 60-6583, which increased CXCL8 protein production Adenosine regulates HSC formation via cAMP-PKA A 2b receptor is commonly coupled to adenylyl cyclase via G protein subunit Gs and increases intracellular cAMP that activates PKA (Fredholm, 2007). We treated HAECs with BAY 60-6583 and performed chemiluminescence assay for cAMP activity.…”

Section: Adenosine Regulates the Formation Of Hscsmentioning

confidence: 99%

Adenosine signaling promotes hematopoietic stem and progenitor cell emergence

Jing¹,

Tamplin²,

Chen³

et al. 2015

J Cell Biol

View full text Add to dashboard Cite

Hematopoietic stem cells (HSCs) emerge from aortic endothelium via the endothelial-tohematopoietic transition (EHT). The molecular mechanisms that initiate and regulate EHT remain poorly understood. Here, we show that adenosine signaling regulates hematopoietic stem and progenitor cell (HSPC) development in zebrafish embryos. The adenosine receptor A 2b is expressed in the vascular endothelium before HSPC emergence. Elevated adenosine levels increased runx1 + /cmyb + HSPCs in the dorsal aorta, whereas blocking the adenosine pathway decreased HSPCs. Knockdown of A 2b adenosine receptor disrupted scl + hemogenic vascular endothelium and the subsequent EHT process. A 2b adenosine receptor activation induced CXCL8 via cAMP-protein kinase A (PKA) and mediated hematopoiesis. We further show that adenosine increased multipotent progenitors in a mouse embryonic stem cell colony-forming assay and in embryonic day 10.5 aorta-gonad-mesonephros explants. Our results demonstrate that adenosine signaling plays an evolutionary conserved role in the first steps of HSPC formation in vertebrates.

show abstract

Adenosine, an endogenous distress signal, modulates tissue damage and repair

Cited by 629 publications

References 79 publications

Physiological roles of A₁ and A_2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine

Physiological roles of A₁ and A_2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine

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

Adenosine signaling promotes hematopoietic stem and progenitor cell emergence

Contact Info

Product

Resources

About