Catecholamine biosynthesis and secretion: physiological and pharmacological effects of secretin.
Catecholamine biosynthesis and secretion: physiological and pharmacological effects of secretin.
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儿茶酚胺生物合成和分泌：促胰液素的生理和药理作用。
DOI：
10.1007/s00441-011-1177-7
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发表时间：
2011
影响因子：
3.6
通讯作者：
Mahata,SushilK
中科院分区：
文献类型：
--
作者：
Mahata,Manjula;Zhang,Kuizing;Gayen,JiaurR;Nandi,Suvobroto;Brar,BhawanjitK;Ghosh,Sajalendu;Mahapatra,NitishR;Taupenot,Laurent;O'Connor,DanielT;Mahata,SushilK
垂体腺苷酸环化酶激活多肽(PACAP)和血管活性肠肽(VIP)可促进酪氨酸羟化酶(TH)的生物合成。我们检测了胰高血糖素/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。促性腺激素激活内源性Th1基因及其转基因启动子(EC50∼4.6nM)在嗜铬细胞瘤细胞中的转录。用促胰液素受体(SCTR)拮抗剂和抑制蛋白激酶A(PKA)、有丝分裂原激活的蛋白激酶或CREB(cAMP反应元件结合蛋白)可取消这种作用。一致认为，分泌素增加了PKA活性，诱导了CREB的磷酸化，并与ThCRE结合，提示分泌素通过PKA-CREB途径向转录发出信号。促性腺激素促PC12细胞分泌儿茶酚胺(EC50PACAP3.5)，但可被∼受体拮抗剂和μ受体拮抗剂抑制。分泌素诱导的分泌不存在细胞外的钙离子，并被细胞内的钙离子螯合所消除。促性腺激素促磷脂酶C(PLC)活性增加，1，4，5-三磷酸肌醇(IP3)水平升高；促性腺激素β抑制促性腺激素分泌儿茶酚胺，提示细胞内钙离子通过磷脂酶途径参与分泌。与PACAP一样，分泌素能激发持久的儿茶酚胺分泌，即使在短暂接触后也是如此。因此，转录是由多肽的纳摩尔浓度触发的，通过SCTR，沿着cAMP-PKA和细胞外信号调节的激酶1/2途径以及通过CREB进行信号传递。相反，只有通过PAC1/VPAC受体的微摩尔浓度的多肽和利用PLC/细胞内钙途径的多肽才能触发分泌。
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 thetyrosine hydroxylase(Th) gene and modulate catecholamine secretion. Secretin activated transcription of the endogenousThgene 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 toThCRE, 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.