Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA.
Nat Metab. 2019 Nov;1(11):1110-1126. doi: 10.1038/s42255-019-0135-7. Epub 2019 Nov 15.
Pancreatic beta cells synthesize and secrete the neurotransmitter γ-aminobutyric acid (GABA) 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 (VRAC), 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 type 1 and type 2 diabetic patients, suggesting that loss of GABA as a synchronizing signal for hormone output may correlate with diabetes pathogenesis.
胰岛β细胞合成并分泌神经递质γ-氨基丁酸（GABA）作为旁分泌和自分泌信号，以帮助调节激素分泌和胰岛稳态。胰岛 GABA 释放通常被描述为囊泡介导的事件。然而，假设的胰岛囊泡 GABA 释放的一个局限性是β细胞中缺乏囊泡 GABA 转运体的表达。因此，GABA 在细胞质中积累。在这里，我们提供的证据表明，人类β细胞以脉冲方式从细胞质池中排出 GABA，为脉冲性胰岛素分泌施加同步节律。由 LRRC8A 或 Swell1 功能编码的容积调节阴离子通道（VRAC）对于脉冲性 GABA 分泌至关重要。β细胞中的 GABA 含量在 1 型和 2 型糖尿病患者的胰岛中被耗尽，并且分泌受到破坏，这表明作为激素输出同步信号的 GABA 的丧失可能与糖尿病发病机制相关。
