Extraordinarily Potent Insulinotropin PACAP : Its Characterization as a Pancreatic Peptide and Action Mechanisms in Islet beta-Cells

极其有效的促胰岛素素 PACAP：其作为胰肽的特性及其在胰岛 β 细胞中的作用机制

基本信息

批准号：
06454147
负责人：
YADA Toshihiko
金额：
$ 4.03万
依托单位：
Kagoshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06454147/
关键词：
PACAP insulin secretion islet autocrine beta-cells PACAP receptor Ca^<2+>受容体サイクリックAMP

项目摘要

Insulin secretion from pancreatic islets is controlled by peptides as well as by nutrients. Two forms of pituitary adenylate cyclase activating polypeptide (PACAP27 and PACAP38) as low as 10^<-13> M stimulated insulin release from rat islets in a glucosedependent manner. PACAP also increased cytosolic Ca^<2+> concentration ( [Ca^<2+>] _i) in islet beta-cells. A blocker of the L-type Ca^<2+> channel abolished both [Ca^<2+>] _i and insulin responses. PACAP stimulated production of cAMP in islets, and a rise in cAMP mimicked PACAP in increasing [Ca^<2+>] _i in beta-cells. Vasoactive intestinal peptide, a peptide exhibiting high amino acid homology with PACAP,also increased [Ca^<2+>] _i in beta-cells but only at concentrations in the nanomolar range, indicating that PACAP27 is 4 logs more potent. High-affinity type-I PACAP receptor was immunohistochemically localized in islets.We next examined the source and physiological role of PACAP in islets. PACAP-immunoreactivity was demonstrated in pancreatic nerve fibers and islets. PACAP mRNA was detected in islets and in the beta-cell line MIN6. Stimulation of insulin release by high glucose from isolated islets was attenuated by a specific PACAP antiserum. The islet incubation medium with high glucose possessed a capacity, which was neutralized by PACAP antiserum, to increase [Ca^<2+>] _i in beta-cells.The results indicate that PACAP reacts with high affinity PACAP-selective receptor and raises cAMP in beta-cells, which in turn enhances the L-type Ca^<2+> channel activity, increases [Ca^<2+>] _i and consequently potentiates glucose-induced insulin release. PACAP is by far the most potent insulinotropic peptide known. Moreover, PACAP is released from islets and acts on islet beta-cells, thus acting as an autocrine hormone. PACAP,via the autocrine action, amplifies glucose-induced insulin secretion in islets, which is characteristically impaired in non-insulin-dependent diabetes mellitus.

胰岛的胰岛素分泌受肽和营养的控制。两种形式的垂体腺苷酸环化酶激活多肽（PACAP27和PACAP38）低至10^<-13> m，以葡萄糖依赖性的方式刺激了大鼠胰岛释放的胰岛素。 PACAP还增加了胰岛β细胞中的胞质Ca^<2+>浓度（[Ca^<2+>] _i）。 L型Ca^<2+>通道的阻滞剂消除了[Ca^<2+>] _i和胰岛素反应。 PACAP刺激了胰岛中的营地的产量，并在β细胞中模仿了[Ca^<2+>] _i的营地的增加。血管活性肠肽是一种与PACAP表现高氨基酸同源性的肽，在β细胞中也增加了[Ca^<2+>] _i，但仅在纳莫尔范围内的浓度下增加，表明PACAP27是4 logs更有效。高亲和力I型PACAP受体在胰岛中被免疫组织化学定位。接下来，我们检查了PACAP在胰岛中的来源和生理作用。胰神经纤维和胰岛中证明了PACAP-免疫反应性。在胰岛和β细胞系MIN6中检测到PACAP mRNA。特定的PACAP抗血清减弱了从分离的胰岛中高葡萄糖刺激胰岛素释放。具有高葡萄糖的胰岛孵育培养基具有由PACAP抗血清中和的能力，可在β细胞中增加[Ca^<2+>] _i。在β细胞又增强了L型Ca^<2+>通道活性的β细胞，增加了[Ca^<2+>] _i，因此增强了葡萄糖诱导的胰岛素释放。 PACAP是迄今为止已知最有效的胰岛素肽。此外，PACAP是从胰岛中释放出来的，并作用于胰岛β细胞，因此充当自分泌激素。 PACAP通过自分泌作用，放大了胰岛中葡萄糖诱导的胰岛素分泌，这在非胰岛素依赖性糖尿病中的特征受损。