Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z3.
J Pharmacol Exp Ther. 2011 Jan;336(1):77-86. doi: 10.1124/jpet.110.171280. Epub 2010 Sep 27.
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 A(2A) 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 A(2A) receptor-selective agonist 2-p-(2-carboxyethyl)phenethylamino-5-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680) augmented ghrelin release concentration-dependently, whereas the A(1) receptor-selective agonist 2-chloro-N(6)-cyclopentyladenosine inhibited ghrelin release. In A(2A) receptor knockout mice, adenosine inhibited ghrelin release, and the A(1) 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 A(1) receptor knockout mice but not in A(2A) receptor knockout mice. Colocalization of ghrelin immunoreactivity with A(1) and A(2A) receptor immunoreactivities in the gastric nerve fibers were observed. Colocalization was also detected for ghrelin and A(1) 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 A(2A) receptor-mediated stimulatory action on gastric ghrelin release, whereas an A(1) receptor-mediated inhibitory action is also apparent when the tonic excitatory effect was removed.
胃泌素，一种从胃中释放的强效食欲激素，在调节能量代谢中起着重要作用。异常的胃泌素水平与饮食失调和代谢疾病有关。然而，调节胃泌素释放的因素仍不清楚。在这里，我们研究了腺苷信号在控制灌胃小鼠胃泌素释放中的作用。腺苷浓度依赖性地刺激胃泌素释放，A(2A)受体选择性拮抗剂 4-(2-[7-氨基-2-(2-呋喃基)[1,2,4]三唑并[2,3-a][1,3,5]三嗪-5-基氨基]乙基)苯酚（ZM 241385）和 2-(2-呋喃基)-7-(2-苯乙基)-7H-吡唑并[4,3-e][1,2,4]三唑并[1,5-c]嘧啶-5-胺（SCH 58261）消除了这种增加的释放。A(2A)受体选择性激动剂 2-p-(2-羧乙基)苯乙氨基-5-N-乙基羧酰胺腺苷盐酸盐（CGS 21680）浓度依赖性地增强胃泌素释放，而 A(1)受体选择性激动剂 2-氯-N(6)-环戊基腺苷抑制胃泌素释放。在 A(2A)受体敲除小鼠中，腺苷抑制胃泌素释放，A(1)受体选择性拮抗剂 8-环戊基-1,3-二丙基黄嘌呤阻断这种抑制。腺苷脱氨酶抑制剂盐酸赤式-9-(2-羟基-3-壬基)腺嘌呤增加了野生型和 A(1)受体敲除小鼠的胃泌素释放，但在 A(2A)受体敲除小鼠中没有增加。在胃神经纤维中观察到胃泌素免疫反应性与 A(1)和 A(2A)受体免疫反应性的共定位。在胃黏膜中也检测到胃泌素和 A(1)受体免疫反应性的共定位。用河豚毒素阻断神经活动消除了腺苷对胃泌素释放的刺激作用。总之，腺苷对胃泌素释放产生主要是紧张的 A(2A)受体介导的刺激作用，而当紧张的兴奋作用被消除时，也存在 A(1)受体介导的抑制作用。
