Acreman Samuel, Ma Jinfang, Denwood Geoffrey, Gao Rui, Tarasov Andrei, Rorsman Patrik, Zhang Quan
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK.
Institute of Neuroscience and Physiology, Department of Physiology, Metabolic Research Unit, Sahlgrenska Academy, University of Gothenburg, Box 430, S-405 30 Gothenburg, Sweden.
iScience. 2024 Apr 5;27(5):109665. doi: 10.1016/j.isci.2024.109665. eCollection 2024 May 17.
Glucagon is secreted by pancreatic α-cells to counteract hypoglycaemia. How glucose regulates glucagon secretion remains unclear. Here, using mouse islets, we studied the role of transmembrane and endoplasmic reticulum (ER) Ca on intrinsic α-cell glucagon secretion. Blocking isradipine-sensitive L-type voltage-gated Ca (Ca) channels abolished α-cell electrical activity but had little impact on its cytosolic Ca oscillations or low-glucose-stimulated glucagon secretion. In contrast, depleting ER Ca with cyclopiazonic acid or blocking ER Ca-releasing ryanodine receptors abolished α-cell glucose sensitivity and low-glucose-stimulated glucagon secretion. ER Ca mobilization in α-cells is regulated by intracellular ATP and likely to be coupled to Ca influx through P/Q-type Ca channels. ω-Agatoxin IVA blocked α-cell ER Ca release and cell exocytosis, but had no additive effect on glucagon secretion when combined with ryanodine. We conclude that glucose regulates glucagon secretion through the control of ER Ca mobilization, a mechanism that can be independent of α-cell electrical activity.
胰高血糖素由胰腺α细胞分泌，以对抗低血糖。葡萄糖如何调节胰高血糖素的分泌仍不清楚。在这里，我们使用小鼠胰岛研究了跨膜和内质网（ER）钙对α细胞内源性胰高血糖素分泌的作用。阻断对异搏定敏感的L型电压门控钙（Ca）通道可消除α细胞的电活动，但对其胞质钙振荡或低葡萄糖刺激的胰高血糖素分泌影响不大。相比之下，用环匹阿尼酸耗尽内质网钙或阻断内质网钙释放的兰尼碱受体可消除α细胞的葡萄糖敏感性和低葡萄糖刺激的胰高血糖素分泌。α细胞内质网钙的动员受细胞内ATP调节，可能与通过P/Q型钙通道的钙内流有关。ω-芋螺毒素IVA阻断α细胞内质网钙释放和细胞胞吐作用，但与兰尼碱联合使用时对胰高血糖素分泌无叠加作用。我们得出结论，葡萄糖通过控制内质网钙动员来调节胰高血糖素分泌，这一机制可能独立于α细胞的电活动。
