Mechanism and effects of pulsatile GABA secretion from cytosolic pools in the human beta cell
Mechanism and effects of pulsatile GABA secretion from cytosolic pools in the human beta cell
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DOI：
10.1038/s42255-019-0135-7
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发表时间：
2019-11-01
影响因子：
20.8
通讯作者：
Phelps, Edward A.
中科院分区：
文献类型：
--
作者：
Menegaz, Danusa;Hagan, D. Walker;Phelps, Edward A.
胰岛β细胞合成和分泌神经递质GABA(伽马氨基丁酸)，作为旁分泌和自分泌信号，帮助调节激素分泌和胰岛动态平衡。胰岛GABA的释放被经典地描述为分泌囊泡介导的事件。然而，假设的囊泡性GABA从胰岛释放的一个限制是在β细胞中缺乏囊泡性GABA转运体的表达。结果，GABA在细胞质中积累。在这里，我们提供了人类β细胞以脉动方式从胞浆池中流出GABA的证据，从而对脉动的胰岛素分泌施加了同步节律。由LRRC8A或Swell1编码的容量调节阴离子通道对GABA的搏动性分泌至关重要。1型和2型糖尿病患者β细胞中GABA含量减少，胰岛分泌中断，提示作为激素输出同步信号的GABA丢失可能与糖尿病的发病机制有关。
Pancreatic beta cells synthesize and secrete the neurotransmitter GABA (gamma-aminobutyric acid) as a paracrine and autocrine signal to help regulate hormone secretion and islet homeostasis. Islet GABA release has classically been described as a secretory-vesicle-mediated event. Yet, a limitation of the hypothesized vesicular GABA release from islets is the lack of expression of a vesicular GABA transporter in beta cells. Consequentially, GABA accumulates in the cytosol. Here, we provide evidence that the human beta cell effluxes GABA from a cytosolic pool in a pulsatile manner, imposing a synchronizing rhythm on pulsatile insulin secretion. The volume regulatory anion channel, functionally encoded by LRRC8A or Swell1, is critical for pulsatile GABA secretion. GABA content in beta cells is depleted and secretion is disrupted in islets from patients with type 1 and type 2 diabetes, suggesting that loss of GABA as a synchronizing signal for hormone output may correlate with diabetes pathogenesis.