Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Agency for Science Technology and Research, Singapore.
PLoS One. 2010 Nov 9;5(11):e15414. doi: 10.1371/journal.pone.0015414.
Insulin secretion is a complex and highly regulated process. It is well established that cytoplasmic calcium is a key regulator of insulin secretion, but how elevated intracellular calcium triggers insulin granule exocytosis remains unclear, and we have only begun to define the identities of proteins that are responsible for sensing calcium changes and for transmitting the calcium signal to release machineries. Synaptotagmins are primarily expressed in brain and endocrine cells and exhibit diverse calcium binding properties. Synaptotagmin-1, -2 and -9 are calcium sensors for fast neurotransmitter release in respective brain regions, while synaptotagmin-7 is a positive regulator of calcium-dependent insulin release. Unlike the three neuronal calcium sensors, whose deletion abolished fast neurotransmitter release, synaptotagmin-7 deletion resulted in only partial loss of calcium-dependent insulin secretion, thus suggesting that other calcium-sensors must participate in the regulation of insulin secretion. Of the other synaptotagmin isoforms that are present in pancreatic islets, the neuronal calcium sensor synaptotagmin-9 is expressed at the highest level after synaptotagmin-7.
METHODOLOGY/PRINCIPAL FINDINGS: In this study we tested whether synaptotagmin-9 participates in the regulation of glucose-stimulated insulin release by using pancreas-specific synaptotagmin-9 knockout (p-S9X) mice. Deletion of synaptotagmin-9 in the pancreas resulted in no changes in glucose homeostasis or body weight. Glucose tolerance, and insulin secretion in vivo and from isolated islets were not affected in the p-S9X mice. Single-cell capacitance measurements showed no difference in insulin granule exocytosis between p-S9X and control mice.
Thus, synaptotagmin-9, although a major calcium sensor in the brain, is not involved in the regulation of glucose-stimulated insulin release from pancreatic β-cells.
胰岛素分泌是一个复杂且高度调控的过程。细胞质钙是胰岛素分泌的关键调节剂，这一点已得到充分证实，但细胞内钙如何引发胰岛素颗粒胞吐仍不清楚，我们才刚刚开始定义负责感知钙变化并将钙信号传递给释放机制的蛋白质的身份。突触融合蛋白主要在脑和内分泌细胞中表达，具有多种钙结合特性。突触融合蛋白-1、-2 和-9 是各自脑区快速神经递质释放的钙传感器，而突触融合蛋白-7 是钙依赖性胰岛素释放的正调节剂。与三个神经元钙传感器不同，其缺失会消除快速神经递质释放，而突触融合蛋白-7 的缺失仅导致钙依赖性胰岛素分泌的部分丧失，因此表明其他钙传感器必须参与胰岛素分泌的调节。在胰岛中存在的其他突触融合蛋白同工型中，神经元钙传感器突触融合蛋白-9 的表达水平仅次于突触融合蛋白-7。
方法/主要发现：在这项研究中，我们使用胰腺特异性突触融合蛋白-9 敲除（p-S9X）小鼠来测试突触融合蛋白-9 是否参与葡萄糖刺激的胰岛素释放的调节。胰腺中突触融合蛋白-9 的缺失对葡萄糖稳态或体重没有影响。p-S9X 小鼠的体内和离体胰岛葡萄糖耐量和胰岛素分泌没有受到影响。单细胞电容测量显示，p-S9X 和对照小鼠之间的胰岛素颗粒胞吐没有差异。
因此，突触融合蛋白-9 虽然是大脑中的主要钙传感器，但不参与调节胰腺β细胞的葡萄糖刺激的胰岛素释放。
