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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到肽和营养素的控制。低至10 -13 M的两种形式的垂体腺苷酸环化酶激活多肽(PACAP27和PACAP38)以葡萄糖依赖性方式刺激大鼠胰岛的胰岛素释放。 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+>通道阻断剂消除了[Ca^<2+>]_i和胰岛素反应。 PACAP刺激胰岛中cAMP的产生，并且cAMP的升高模仿PACAP在β细胞中增加的[Ca 2+ ] _i 。血管活性肠肽，一种与PACAP表现出高氨基酸同源性的肽，也增加β细胞中的[Ca 2+ ]_i，但仅在纳摩尔范围内的浓度，这表明PACAP27的效力高出4个对数。高亲和力 I 型 PACAP 受体通过免疫组织化学定位于胰岛。接下来我们研究了 PACAP 在胰岛中的来源和生理作用。 PACAP 免疫反应性在胰腺神经纤维和胰岛中得到证实。在胰岛和 β 细胞系 MIN6 中检测到 PACAP mRNA。特定的 PACAP 抗血清减弱了来自分离胰岛的高葡萄糖对胰岛素释放的刺激。高糖胰岛培养液具有增加β细胞中[Ca^<2+>]_i的能力，经PACAP抗血清中和后，结果表明，PACAP与高亲和力PACAP选择性受体发生反应，使β细胞中cAMP升高，从而增强L型Ca^<2+>通道活性，增加[Ca^<2+>]_i，从而提高β细胞中的cAMP水平。增强葡萄糖诱导的胰岛素释放。 PACAP 是迄今为止已知的最有效的促胰岛素肽。此外，PACAP 从胰岛释放并作用于胰岛β细胞，从而起到自分泌激素的作用。 PACAP 通过自分泌作用，放大葡萄糖诱导的胰岛胰岛素分泌，而胰岛分泌的胰岛素在非胰岛素依赖型糖尿病中通常会受到损害。