Acyl-Ghrelin Influences Pancreatic β-Cell Function by Interference with KATP Channels
Acyl-Ghrelin Influences Pancreatic β-Cell Function by Interference with KATP Channels
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DOI：
10.2337/db20-0231
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发表时间：
2021-02-01
期刊：
影响因子：
7.7
通讯作者：
Drews, Gisela
中科院分区：
文献类型：
--
作者：
Kaiser, Julia;Krippeit-Drews, Peter;Drews, Gisela
本研究的目的是阐明下丘脑饥饿诱导激素酰基-生长激素释放肽（AG）（也在胰腺中产生）如何影响β细胞功能，特别关注ATP敏感性K+（K-ATP）通道的作用和激素的确切作用部位。AG使膜电位超极化并降低细胞质钙浓度[Ca 2 +]（c）和葡萄糖刺激的胰岛素分泌（GSIS）。这些效应在来自SUR 1敲除（KO）小鼠的β细胞中被消除。AG增加K-ATP电流，但仅在一个完整的代谢配置。未酰化的ghrelin抵消了AG的作用。AG对膜电位和GSIS的影响只能在Ghrelin受体（GHSR 1a）拮抗剂和反向激动剂的联合存在下才能避免。AG对GSIS的抑制作用可被二丁酰环cAMP或3-异丁基-1-甲基黄嘌呤及生长抑素（SST）2-5受体拮抗剂H6056所阻断。这些数据表明，AG可能通过干扰cAMP/cAMP依赖性蛋白激酶途径间接开放K-ATP通道，导致[Ca 2 +]（c）和GSIS降低。使用SUR 1-KO β细胞的实验表明AG对β细胞的直接作用，而不是如前所述，AG诱导的SST从δ细胞释放的排他性作用。然而，SST受体可能参与AG的作用，可能是通过AG和SST受体的异聚化。
The aim for this study was to elucidate how the hypothalamic hunger-inducing hormone acyl-ghrelin (AG), which is also produced in the pancreas, affects beta-cell function, with particular attention to the role of ATP-sensitive K+ (K-ATP) channels and the exact site of action of the hormone. AG hyperpolarized the membrane potential and decreased cytoplasmic calcium concentration [Ca2+](c) and glucose-stimulated insulin secretion (GSIS). These effects were abolished in beta-cells from SUR1-knockout (KO) mice. AG increased K-ATP current but only in a configuration with intact metabolism. Unacylated ghrelin counteracted the effects of AG. The influence of AG on membrane potential and GSIS could only be averted in the combined presence of a ghrelin receptor (GHSR1a) antagonist and an inverse agonist. The inhibition of GSIS by AG could be prevented by dibutyryl cyclic-cAMP or 3-isobutyl-1-methylxanthine and the somatostatin (SST) receptor 2-5 antagonist H6056. These data indicate that AG indirectly opens K-ATP channels probably by interference with the cAMP/cAMP-dependent protein kinase pathway, resulting in a decrease of [Ca2+](c) and GSIS. The experiments with SUR1-KO beta-cells point to a direct effect of AG on beta-cells and not, as earlier suggested, to an exclusive effect by AG-induced SST release from delta-cells. Nevertheless, SST receptors may be involved in the effect of AG, possibly by heteromerization of AG and SST receptors.