DiMaggio D A, Farah J M, Westfall T C
Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, Missouri 63104.
Endocrinology. 1994 Feb;134(2):719-27. doi: 10.1210/endo.134.2.8299567.
Undifferentiated rat pheochromocytoma PC12 cells resemble immature adrenal chromaffin cells, express neuropeptide-Y (NPY) receptors of the Y1 subtype, and synthesize catecholamines as well as NPY. In the present study, we examined how phenotypic alteration of PC12 cells by nerve growth factor (NGF) or glucocorticoid affected cellular responsiveness to NPY and related agonists, especially with regard to modulation of catecholamine overflow. Unlike undifferentiated PC12 cells, cells differentiated to a sympathetic neuronal phenotype with NGF were responsive to the Y2 receptor-selective agonist, NPY 13-36. NPY 13-36 1) inhibited binding of [125I]NPY 1-36, 2) inhibited accumulation of evoked cAMP, and 3) inhibited evoked catecholamine overflow. NGF-differentiated cells were also responsive to the Y1 receptor-selective agonist [Leu31,Pro34]NPY (LP-NPY). Like NPY-(13-36), LP-NPY inhibited binding of [125I]NPY-(1-36); however, LP-NPY and NPY-(13-36) exerted their effects through heterogeneous receptors, as LP-NPY enhanced while NPY 13-36 inhibited evoked catecholamine overflow in NGF-differentiated cells, despite the fact that both agonists inhibited the evoked cAMP. In contrast to NGF-differentiated cells, cells differentiated to a mature chromaffin phenotype with dexamethasone were unresponsive to NPY-(13-36), nor did the Y2 agonist inhibit binding of [125I]NPY-(1-36). Dexamethasone-differentiated PC12 cells were, however, responsive to LP-NPY, as this agonist enhanced evoked catecholamine overflow and inhibited binding of [125I]NPY-(1-36). Peptide-YY also enhanced catecholamine overflow, but only significantly at 100 nM. The data suggest differential expression of NPY receptor subtypes on neuronal and endocrine cells where catecholamine overflow is a key feature. These studies further demonstrate inhibitory or excitatory modulation of catecholamine transmission by NPY via distinct receptor subtypes in homogeneous sympathoadrenomedullary models resembling sympathetic neurons and chromaffin cells.
未分化的大鼠嗜铬细胞瘤PC12细胞类似于未成熟的肾上腺嗜铬细胞，表达Y1亚型的神经肽Y（NPY）受体，并合成儿茶酚胺以及NPY。在本研究中，我们研究了神经生长因子（NGF）或糖皮质激素对PC12细胞的表型改变如何影响细胞对NPY及相关激动剂的反应性，特别是在儿茶酚胺释放的调节方面。与未分化的PC12细胞不同，用NGF分化为交感神经元表型的细胞对Y2受体选择性激动剂NPY 13 - 36有反应。NPY 13 - 36：1）抑制[125I]NPY 1 - 36的结合；2）抑制诱发的cAMP积累；3）抑制诱发的儿茶酚胺释放。NGF分化的细胞对Y1受体选择性激动剂[Leu31,Pro34]NPY（LP - NPY）也有反应。与NPY -（13 - 36）一样，LP - NPY抑制[125I]NPY -（1 - 36）的结合；然而，LP - NPY和NPY -（13 - 36）通过不同的受体发挥作用，因为尽管两种激动剂都抑制诱发的cAMP，但在NGF分化的细胞中，LP - NPY增强而NPY 13 - 36抑制诱发的儿茶酚胺释放。与NGF分化的细胞相反，用地塞米松分化为成熟嗜铬细胞表型的细胞对NPY -（13 - 36）无反应，Y2激动剂也不抑制[125I]NPY -（1 - 36）的结合。然而，地塞米松分化的PC12细胞对LP - NPY有反应，因为该激动剂增强诱发的儿茶酚胺释放并抑制[125I]NPY -（1 - 36）的结合。肽YY也增强儿茶酚胺释放，但仅在100 nM时具有显著作用。数据表明，在儿茶酚胺释放是关键特征的神经元和内分泌细胞上，NPY受体亚型存在差异表达。这些研究进一步证明，在类似于交感神经元和嗜铬细胞的同质性交感肾上腺髓质模型中，NPY通过不同的受体亚型对儿茶酚胺传递进行抑制或兴奋调节。
