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首页> 外文期刊>Cell and Tissue Research >Catecholamine biosynthesis and secretion: physiological and pharmacological effects of secretin
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Catecholamine biosynthesis and secretion: physiological and pharmacological effects of secretin

机译：儿茶酚胺的生物合成与分泌：促胰液素的生理和药理作用

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摘要

Pituitary adenylyl cyclase activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) augment the biosynthesis of tyrosine hydroxylase (TH). We tested whether secretin belonging to the glucagon/PACAP/VIP superfamily would increase transcription of the tyrosine hydroxylase (Th) gene and modulate catecholamine secretion. Secretin activated transcription of the endogenous Th gene and its transfected promoter (EC50 ∼4.6 nM) in pheochromocytoma (PC12) cells. This was abolished by pre-treatment with a secretin receptor (SCTR) antagonist and by inhibition of protein kinase A (PKA), mitogen-activated protein kinase, or CREB (cAMP response element-binding protein). In agreement, secretin increased PKA activity and induced phosphorylation of CREB and binding to Th CRE, suggesting secretin signaling to transcription via a PKA-CREB pathway. Secretin stimulated catecholamine secretion (EC50 ∼3.5 μM) from PC12 cells, but this was inhibited by pre-treatment with VIP-preferring receptor (VPAC1)/PACAP-preferring receptor (PAC1) antagonists. Secretin-evoked secretion occurred without extracellular Ca2+ and was abolished by intracellular Ca2+ chelation. Secretin augmented phospholipase C (PLC) activity and increased inositol-1,4,5-triphosphate (IP3) levels in PC12 cells; PLC-β inhibition blocked secretin-induced catecholamine secretion, indicating the participation of intracellular Ca2+ from a phospholipase pathway in secretion. Like PACAP, secretin evoked long-lasting catecholamine secretion, even after only a transient exposure. Thus, transcription is triggered by nanomolar concentrations of the peptide through SCTR, with signaling along the cAMP-PKA and extracellular-signal-regulated kinase 1/2 pathways and through CREB. By contrast, secretion is triggered only by micromolar concentrations of peptide through PAC1/VPAC receptors and by utilizing a PLC/intracellular Ca2+ pathway.
机译：垂体腺苷酸环化酶激活多肽（PACAP）和血管活性肠多肽（VIP）增强了酪氨酸羟化酶（TH）的生物合成。我们测试了属于胰高血糖素/ PACAP / VIP超家族的促胰液素是否会增加酪氨酸羟化酶（Th）基因的转录并调节儿茶酚胺的分泌。促胰液素激活嗜铬细胞瘤（PC12）细胞内源性Th基因及其转染的启动子（EC 50 〜4.6 nM）的转录。通过用促胰液素受体（SCTR）拮抗剂进行预处理，并通过抑制蛋白激酶A（PKA），促分裂原活化蛋白激酶或CREB（cAMP反应元件结合蛋白），可以消除这种情况。一致的是，促胰液素增加PKA活性并诱导CREB磷酸化并与Th CRE结合，提示促胰液素通过PKA-CREB途径转录。促胰液素刺激PC12细胞分泌儿茶酚胺分泌（EC 50 〜3.5μM），但通过VIP优先受体（VPAC1）/ PACAP优先受体（PAC1）拮抗剂预处理可抑制其分泌。分泌素诱发的分泌在没有细胞外Ca 2 + 的情况下发生，并被细胞内Ca 2 + 螯合消除。促胰液素增加PC12细胞中磷脂酶C（PLC）的活性并增加肌醇-1,4,5-三磷酸（IP 3 ）的水平； PLC-β的抑制作用阻断了促胰液素诱导的儿茶酚胺的分泌，表明细胞内Ca 2 + 通过磷脂酶途径参与分泌。像PACAP一样，即使只是短暂暴露，促胰液素也会引起持久的儿茶酚胺分泌。因此，转录是通过肽的纳摩尔浓度通过SCTR，沿cAMP-PKA和细胞外信号调节的激酶1/2途径以及通过CREB的信号传导而触发的。相比之下，分泌仅由通过PAC1 / VPAC受体的微摩尔浓度的肽和利用PLC /细胞内Ca 2 + 途径触发。

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