Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37232, USA; Center for Stem Cell Biology, Vanderbilt University School of Medicine, Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37232, USA; The Program of Developmental Biology, Vanderbilt University School of Medicine, Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37232, USA.
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37232, USA.
Dev Cell. 2018 May 7;45(3):347-361.e5. doi: 10.1016/j.devcel.2018.03.013. Epub 2018 Apr 12.
Islet β cells from newborn mammals exhibit high basal insulin secretion and poor glucose-stimulated insulin secretion (GSIS). Here we show that β cells of newborns secrete more insulin than adults in response to similar intracellular Ca concentrations, suggesting differences in the Ca sensitivity of insulin secretion. Synaptotagmin 4 (Syt4), a non-Ca binding paralog of the β cell Ca sensor Syt7, increased by ∼8-fold during β cell maturation. Syt4 ablation increased basal insulin secretion and compromised GSIS. Precocious Syt4 expression repressed basal insulin secretion but also impaired islet morphogenesis and GSIS. Syt4 was localized on insulin granules and Syt4 levels inversely related to the number of readily releasable vesicles. Thus, transcriptional regulation of Syt4 affects insulin secretion; Syt4 expression is regulated in part by Myt transcription factors, which repress Syt4 transcription. Finally, human SYT4 regulated GSIS in EndoC-βH1 cells, a human β cell line. These findings reveal the role that altered Ca sensing plays in regulating β cell maturation.
新生哺乳动物的胰岛β细胞表现出高基础胰岛素分泌和较差的葡萄糖刺激胰岛素分泌（GSIS）。在这里，我们发现新生β细胞对相似的细胞内 Ca 浓度的胰岛素分泌比成人更多，这表明胰岛素分泌的 Ca 敏感性存在差异。突触结合蛋白 4（Syt4）是β细胞 Ca 传感器 Syt7 的非 Ca 结合同源物，在β细胞成熟过程中增加了约 8 倍。Syt4 的缺失增加了基础胰岛素的分泌并损害了 GSIS。早熟的 Syt4 表达抑制了基础胰岛素的分泌，但也损害了胰岛的形态发生和 GSIS。Syt4 定位于胰岛素颗粒上，Syt4 水平与可快速释放的囊泡数量呈反比。因此，Syt4 的转录调控影响胰岛素的分泌；Syt4 的表达部分受到 Myt 转录因子的调节，这些转录因子抑制 Syt4 的转录。最后，人 SYT4 调节 EndoC-βH1 细胞（一种人β细胞系）的 GSIS。这些发现揭示了改变的 Ca 感应在调节β细胞成熟中的作用。
