Newcomer insulin secretory granules as a highly calcium-sensitive pool
Newcomer insulin secretory granules as a highly calcium-sensitive pool
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DOI：
10.1073/pnas.0901202106
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发表时间：
2009-05-05
影响因子：
11.1
通讯作者：
Sherman, Arthur
中科院分区：
文献类型：
--
作者：
Pedersen, Morten Gram;Sherman, Arthur
胰岛素分泌是响应于葡萄糖刺激中的步骤的双相的。最近的实验表明，2个不同的机制在2个阶段，短暂的第一阶段分泌由于停靠颗粒的胞吐作用，但第二个持续阶段主要是由于新来的颗粒。另一系列研究表明，存在2个具有不同Ca 2+敏感性的可释放颗粒库。立即释放池（IRP）位于Ca 2+通道附近，而高度Ca 2+敏感池（HCSP）主要位于远离Ca 2+通道的位置。我们通过添加HCSP扩展了先前的胞吐和胰岛素释放模型，并表明包含该池自然导致胰岛素分泌主要来自分泌的第二阶段期间的新颗粒。我们表明，该模型是兼容的数据从单细胞上的HCSP和刺激胰岛葡萄糖，包括L-和R-型Ca 2+通道敲除，以及从Syntaxin-1A缺陷的细胞。我们还使用该模型来研究钙信号和池消耗在控制双相分泌中的相对贡献。
Insulin secretion is biphasic in response to a step in glucose stimulation. Recent experiments suggest that 2 different mechanisms operate during the 2 phases, with transient first-phase secretion due to exocytosis of docked granules but the second sustained phase due largely to newcomer granules. Another line of research has shown that there exist 2 pools of releasable granules with different Ca2+ sensitivities. An immediately releasable pool (IRP) is located in the vicinity of Ca2+ channels, whereas a highly Ca2+-sensitive pool (HCSP) resides mainly away from Ca2+ channels. We extend a previous model of exocytosis and insulin release by adding an HCSP and show that the inclusion of this pool naturally leads to insulin secretion mainly from newcomer granules during the second phase of secretion. We show that the model is compatible with data from single cells on the HCSP and from stimulation of islets by glucose, including L- and R-type Ca2+ channel knockouts, as well as from Syntaxin-1A-deficient cells. We also use the model to investigate the relative contribution of calcium signaling and pool depletion in controlling biphasic secretion.