Department of Pharmacology, Shanxi Medical University, Taiyuan 030001, China.
Department of Pharmacology, Shanxi Medical University, Taiyuan 030001, China; Department of Endocrinology, the First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China.
Cell Signal. 2019 Sep;61:48-56. doi: 10.1016/j.cellsig.2019.05.006. Epub 2019 May 11.
Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) plays a crucial role in the endocrine system. The present study aimed to investigate the effect of PACAP38 on insulin secretion and the underlying mechanism in rat pancreatic β-cells. The insulin secretion results showed that PACAP38 stimulated insulin secretion in a glucose- and dose-dependent manner. The insulinotropic effect was mediated by PAC receptor, but not by VPAC and VPAC receptors. Inhibition of adenylyl cyclase and protein kinase A suppressed PACAP38-augmented insulin secretion. Glucose-regulated insulin secretion is dependent on a series of electrophysiological activities. Current-clamp technology suggested that PACAP38 prolonged action potential duration. Voltage-clamp recordings revealed that PACAP38 blocked voltage-dependent potassium currents, and this effect was reversed by inhibition of PAC receptor, adenylyl cyclase, or protein kinase A. Activation of Ca channels by PACAP38 was also observed, which could be antagonized by the PAC receptor antagonist. In addition, calcium-imaging analysis indicated that PACAP38 increased intracellular Ca concentration, which was decreased by PAC receptor antagonist. These findings demonstrate that PACAP38 stimulates glucose-induced insulin secretion mainly by acting on PAC receptor, inhibiting voltage-dependent potassium channels, activating Ca channels and increasing intracellular Ca concentration. Further, PACAP blocks voltage-dependent potassium currents via the adenylyl cyclase/protein kinase A signaling pathway.
垂体腺苷酸环化酶激活肽（PACAP）在内分泌系统中发挥着关键作用。本研究旨在探讨 PACAP38 对大鼠胰岛β细胞胰岛素分泌的影响及其潜在机制。胰岛素分泌结果表明，PACAP38 以葡萄糖和剂量依赖的方式刺激胰岛素分泌。胰岛素促分泌作用是由 PAC 受体介导的，但不是由 VPAC 和 VPAC 受体介导的。抑制腺苷酸环化酶和蛋白激酶 A 可抑制 PACAP38 增强的胰岛素分泌。葡萄糖调节的胰岛素分泌依赖于一系列电生理活动。电流钳技术表明，PACAP38 延长动作电位持续时间。电压钳记录显示，PACAP38 阻断电压依赖性钾电流，而 PAC 受体、腺苷酸环化酶或蛋白激酶 A 的抑制可逆转这种作用。还观察到 PACAP38 激活钙通道，而 PAC 受体拮抗剂可拮抗这种作用。此外，钙成像分析表明，PACAP38 增加细胞内 Ca 浓度，而 PAC 受体拮抗剂可降低细胞内 Ca 浓度。这些发现表明，PACAP38 主要通过作用于 PAC 受体、抑制电压依赖性钾通道、激活钙通道和增加细胞内 Ca 浓度来刺激葡萄糖诱导的胰岛素分泌。此外，PACAP 通过腺苷酸环化酶/蛋白激酶 A 信号通路阻断电压依赖性钾电流。
