PDF(Pubmed)
Abstract：
Epinephrine influences the function of pancreatic β-cells, primarily through the α2A-adrenergic receptor (α2A-AR) on their plasma membrane. Previous studies indicate that epinephrine transiently suppresses insulin secretion, whereas prolonged exposure induces its compensatory secretion. Nonetheless, the impact of epinephrine-induced α2A-AR signaling on the survival and function of pancreatic β-cells, particularly the impact of reprogramming after their removal from sustained epinephrine stimulation, remains elusive. In the present study, we applied MIN6, a murine insulinoma cell line, with 3 days of high concentration epinephrine incubation and 2 days of standard incubation, explored cell function and activity, and analyzed relevant regulatory pathways. The results showed that chronic epinephrine incubation led to the desensitization of α2A-AR and enhanced insulin secretion. An increased number of docked insulin granules and impaired Syntaxin-2 was found after chronic epinephrine exposure. Growth curve and cell cycle analyses showed the inhibition of cell proliferation. Transcriptome analysis showed the occurrence of endoplasmic reticulum stress (ER stress) and oxidative stress, such as the presence of BiP, CHOP, IRE1, ATF4, and XBP, affecting cellular endoplasmic reticulum function and survival, along with UCP2, OPA1, PINK, and PRKN, associated with mitochondrial dysfunction. Consequently, we conclude that chronic exposure to epinephrine induces α2A-AR desensitization and leads to ER and oxidative stress, impairing protein processing and mitochondrial function, leading to modified pancreatic β-cell secretory function and cell fate.
摘要：
肾上腺素影响胰腺β细胞的功能，主要通过其质膜上的α2A-肾上腺素能受体（α2A-AR）。以前的研究表明，肾上腺素短暂抑制胰岛素分泌，而长期暴露诱导其代偿分泌。尽管如此，肾上腺素诱导的α2A-AR信号对胰岛β细胞存活和功能的影响,特别是在从持续的肾上腺素刺激中去除后重新编程的影响，仍然难以捉摸。在本研究中,我们应用了小鼠胰岛素瘤细胞系MIN6，高浓度肾上腺素孵育3天，标准孵育2天，探索细胞功能和活动，并分析了相关的调控途径。结果表明，慢性肾上腺素孵育导致α2A-AR脱敏并增强胰岛素分泌。慢性肾上腺素暴露后，发现对接的胰岛素颗粒和Syntaxin-2受损的数量增加。生长曲线和细胞周期分析显示细胞增殖受到抑制。转录组分析显示内质网应激(ER应激)和氧化应激,例如BiP的存在，CHOP,IRE1、ATF4和XBP，影响细胞内质网功能和存活，随着UCP2，OPA1，粉红色，和PRKN,与线粒体功能障碍有关。因此,我们得出结论，慢性暴露于肾上腺素诱导α2A-AR脱敏并导致ER和氧化应激，损伤蛋白质加工和线粒体功能，导致胰腺β细胞分泌功能和细胞命运的改变。
