O'Shea D, Morgan D G, Meeran K, Edwards C M, Turton M D, Choi S J, Heath M M, Gunn I, Taylor G M, Howard J K, Bloom C I, Small C J, Haddo O, Ma J J, Callinan W, Smith D M, Ghatei M A, Bloom S R
Department of Medicine, Hammersmith Hospital, Royal Postgraduate Medical School, London, United Kingdom.
Endocrinology. 1997 Jan;138(1):196-202. doi: 10.1210/endo.138.1.4899.
There are now six recognized neuropeptide Y (NPY) receptor subtypes (Y1-Y4 and two recently cloned distinct receptors labeled Y5), of which Y1 and one of the Y5's have been suggested could mediate the effect of NPY on feeding. The fragments NPY(2-36) and NPY(3-36), which bind Y1 only poorly, were injected intracerebroventricularly (icv) and found to have similar dose-response relationships to NPY in the stimulation of feeding. However NPY (13-36), which stimulates both Y2 and Y5, caused no increase in food intake, even at high doses. Maximal stimulation with the classical Y1 agonist [Pro34]-NPY produced only 50% of the maximum effect of NPY itself despite fully inhibiting adenylyl cyclase activity in vitro in a Y1 system. The novel fragment [Pro34]-NPY(3-36) is as effective at stimulating food intake as the classical Y1 analogue [Pro34]-NPY but bound to the Y1 receptor with only 1/20th of the affinity of NPY and failed to inhibit adenylyl cyclase through this receptor. [Pro34]-NPY(3-36) is therefore a relatively appetite-selective ligand. Coadministration of high dose NPY(13-36) and [Pro34]NPY did not enhance feeding compared with [Pro34]-NPY alone. In addition, the NPY Y1 receptor antagonist BIBP-3226, which does not bind Y2, Y4, or Y5 receptors, significantly reduced NPY induced feeding. These results indicate that the feeding effect of icv NPY involves a novel receptor and that it is functionally distinct from the recognized receptor subtypes.
目前已确认存在六种神经肽Y（NPY）受体亚型（Y1 - Y4以及最近克隆出的两种不同的受体，标记为Y5），其中Y1和一种Y5亚型被认为可能介导NPY对进食的影响。NPY(2 - 36)和NPY(3 - 36)片段与Y1的结合能力很差，将它们脑室内注射（icv）后发现，在刺激进食方面，它们与NPY具有相似的剂量 - 反应关系。然而，能同时刺激Y2和Y5的NPY(13 - 36)，即使高剂量注射也不会引起食物摄入量增加。经典的Y1激动剂[Pro34]-NPY即使在体外Y1系统中能完全抑制腺苷酸环化酶活性，其最大刺激作用也仅产生NPY自身最大效应的50%。新型片段[Pro34]-NPY(3 - 36)在刺激食物摄入方面与经典的Y1类似物[Pro34]-NPY一样有效，但与Y1受体的结合亲和力仅为NPY的1/20，且无法通过该受体抑制腺苷酸环化酶。因此，[Pro34]-NPY(3 - 36)是一种相对具有食欲选择性的配体。与单独使用[Pro34]-NPY相比，高剂量的NPY(13 - 36)与[Pro34]NPY共同给药并没有增强进食效果。此外，不与Y2、Y4或Y5受体结合的NPY Y1受体拮抗剂BIBP - 3226能显著降低NPY诱导的进食。这些结果表明，脑室内注射NPY的进食效应涉及一种新型受体，并且在功能上与已确认的受体亚型不同。
