Synaptotagmin-7 is a principal Ca2+ sensor for Ca2+-induced glucagon exocytosis in pancreas
Synaptotagmin-7 is a principal Ca2+ sensor for Ca2+-induced glucagon exocytosis in pancreas
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DOI：
10.1113/jphysiol.2008.168005
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发表时间：
2009-03-15
影响因子：
5.5
通讯作者：
Han, Weiping
中科院分区：
文献类型：
--
作者：
Gustavsson, Natalia;Wei, Shun-Hui;Han, Weiping
激素如胰高血糖素是由Ca 2+诱导的大致密核心囊泡的胞吐分泌的，但所涉及的机制仅部分阐明。对胰腺β细胞分泌胰岛素的研究表明，单独的突触结合蛋白-7不足以介导Ca 2+依赖性胰岛素颗粒胞吐作用，对嗜铬细胞分泌神经肽和儿茶酚胺的研究表明，突触结合蛋白-1和-7作为Ca 2+传感器协同胞吐作用，并且两者同等参与。由于没有其他肽分泌进行了分析，目前还不清楚是否synaptotagmins一般作为Ca 2+传感器在大致密核心囊泡胞吐内分泌细胞，如果是这样的话，是否synaptotagmin-7总是功能与合作伙伴的作用。特别是，尽管胰岛素和胰高血糖素一起调节血糖水平，但对Ca 2+触发的胰高血糖素从α细胞释放的机制了解远少于从β细胞分泌胰岛素的机制。为了解决这些问题，我们分析了突触结合蛋白在Ca 2+触发的胰高血糖素胞吐中的作用。令人惊讶的是，我们发现，删除一个单一的突触结合蛋白亚型，突触结合蛋白-7，几乎废除了Ca 2+触发的胰高血糖素分泌。此外，单细胞电容测量证实，胰腺α细胞缺乏synaptotagmin-7表现出很少的Ca 2+诱导的胞吐，而所有其他生理和形态参数的α细胞是正常的。因此，我们的数据确定synaptotagmin-7是胰高血糖素分泌的主要Ca 2+传感器，并支持synaptotagmin作为神经递质、神经肽和激素分泌中单独作用的Ca 2+传感器执行普遍但选择性功能的观点。
Hormones such as glucagon are secreted by Ca2+-induced exocytosis of large dense-core vesicles, but the mechanisms involved have only been partially elucidated. Studies of pancreatic beta-cells secreting insulin revealed that synaptotagmin-7 alone is not sufficient to mediate Ca2+-dependent insulin granule exocytosis, and studies of chromaffin cells secreting neuropeptides and catecholamines showed that synaptotagmin-1 and -7 collaborate as Ca2+ sensors for exocytosis, and that both are equally involved. As no other peptide secretion was analysed, it remains unclear whether synaptotagmins generally act as Ca2+ sensors in large dense-core vesicle exocytosis in endocrine cells, and if so, whether synaptotagmin-7 always functions with a partner in that role. In particular, far less is known about the mechanisms underlying Ca2+-triggered glucagon release from alpha-cells than insulin secretion from beta-cells, even though insulin and glucagon together regulate blood glucose levels. To address these issues, we analysed the role of synaptotagmins in Ca2+-triggered glucagon exocytosis. Surprisingly, we find that deletion of a single synaptotagmin isoform, synaptotagmin-7, nearly abolished Ca2+-triggered glucagon secretion. Moreover, single-cell capacitance measurements confirmed that pancreatic alpha-cells lacking synaptotagmin-7 exhibited little Ca2+-induced exocytosis, whereas all other physiological and morphological parameters of the alpha-cells were normal. Our data thus identify synaptotagmin-7 as a principal Ca2+ sensor for glucagon secretion, and support the notion that synaptotagmins perform a universal but selective function as individually acting Ca2+ sensors in neurotransmitter, neuropeptide, and hormone secretion.