Abstract
Ghrelin, a potent orexigenic hormone released from the stomach, is important in regulating energy metabolism. Abnormal ghrelin levels are associated with eating disorders and metabolic diseases. However, factors involved in the regulation of ghrelin release remain unclear. Here, we examined the involvement of adenosine signaling in the control of ghrelin release from the perfused mouse stomach. Adenosine stimulated ghrelin release concentration-dependently, and the A2A receptor-selective antagonists 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) and 2-(2-furanyl)-7-(2-phenylethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine (SCH 58261) abolished the increased release. The A2A receptor-selective agonist 2-p-(2-carboxyethyl)phenethylamino-5-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680) augmented ghrelin release concentration-dependently, whereas the A1 receptor-selective agonist 2-chloro-N6-cyclopentyladenosine inhibited ghrelin release. In A2A receptor knockout mice, adenosine inhibited ghrelin release, and the A1 receptor-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine blocked this inhibition. The adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride increased ghrelin release in wild-type and A1 receptor knockout mice but not in A2A receptor knockout mice. Colocalization of ghrelin immunoreactivity with A1 and A2A receptor immunoreactivities in the gastric nerve fibers were observed. Colocalization was also detected for ghrelin and A1 receptor immunoreactivities in the gastric mucosa. Blockade of neural activities with tetrodotoxin abolished the stimulatory effect of adenosine on ghrelin release. In conclusion, adenosine exerts predominantly a tonic A2A receptor-mediated stimulatory action on gastric ghrelin release, whereas an A1 receptor-mediated inhibitory action is also apparent when the tonic excitatory effect was removed.
Footnotes
This study was supported by the Wah Sheung Fund. G.K.Y. is a recipient of a Alexander Graham Bell Canada Graduate Scholarship from the Natural Sciences and Engineering Research Council of Canada. T.J.K. is a Senior Scholar of the Michael Smith Foundation for Health Research and received grant funding from the Canadian Institutes of Health Research and the Michael Smith Foundation for Health Research.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.171280.
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ABBREVIATIONS:
- A1R
- adenosine A1 receptor
- A2AR
- adenosine A2A receptor
- KO
- knockout
- Ado
- adenosine
- ANOVA
- analysis of variance
- CCPA
- 2-chloro-N6-cyclopentyladenosine
- CGS 21680
- 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride
- DPCPX
- 8-cyclopentyl-1,3-dipropylxanthine
- ZM 241385
- 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol
- EHNA
- erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride
- IB-MECA
- 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-β-d-ribofuranuronamide
- NECA
- 5'-N-ethylcarboxamidoadenosine
- TTX
- tetrodotoxin
- SCH 58261
- 2-(2-furanyl)-7-(2-phenylethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine
- GLP-1
- glucose-dependent insulinotropic polypeptide
- RIA
- radioimmunoassay
- IR
- immunoreactivity
- PGP 9.5
- protein gene product 9.5.
- Received June 9, 2010.
- Accepted September 22, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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