Bertolino Philippe, Holmberg Rebecka, Reissmann Eva, Andersson Olov, Berggren Per-Olof, Ibáñez Carlos F
Division of Molecular Neurobiology, Department of Neuroscience, Karolinska Institutet, S-17177 Stockholm, Sweden.
Proc Natl Acad Sci U S A. 2008 May 20;105(20):7246-51. doi: 10.1073/pnas.0801285105. Epub 2008 May 14.
All major cell types in pancreatic islets express the transforming growth factor (TGF)-beta superfamily receptor ALK7, but the physiological function of this receptor has been unknown. Mutant mice lacking ALK7 showed normal pancreas organogenesis but developed an age-dependent syndrome involving progressive hyperinsulinemia, reduced insulin sensitivity, liver steatosis, impaired glucose tolerance, and islet enlargement. Hyperinsulinemia preceded the development of any other defect, indicating that this may be one primary consequence of the lack of ALK7. In agreement with this, mutant islets showed enhanced insulin secretion under sustained glucose stimulation, indicating that ALK7 negatively regulates glucose-stimulated insulin release in beta-cells. Glucose increased expression of ALK7 and its ligand activin B in islets, but decreased that of activin A, which does not signal through ALK7. The two activins had opposite effects on Ca(2+) signaling in islet cells, with activin A increasing, but activin B decreasing, glucose-stimulated Ca(2+) influx. On its own, activin B had no effect on WT cells, but stimulated Ca(2+) influx in cells lacking ALK7. In accordance with this, mutant mice lacking activin B showed hyperinsulinemia comparable with that of Alk7(-/-) mice, but double mutants showed no additive effects, suggesting that ALK7 and activin B function in a common pathway to regulate insulin secretion. These findings uncover an unexpected antagonism between activins A and B in the control of Ca(2+) signaling in beta-cells. We propose that ALK7 plays an important role in regulating the functional plasticity of pancreatic islets, negatively affecting beta-cell function by mediating the effects of activin B on Ca(2+) signaling.
胰岛中的所有主要细胞类型均表达转化生长因子（TGF）-β超家族受体ALK7，但该受体的生理功能尚不清楚。缺乏ALK7的突变小鼠胰腺器官发生正常，但出现了一种年龄依赖性综合征，包括进行性高胰岛素血症、胰岛素敏感性降低、肝脂肪变性、糖耐量受损和胰岛肿大。高胰岛素血症先于任何其他缺陷出现，表明这可能是缺乏ALK7的一个主要后果。与此一致的是，突变胰岛在持续葡萄糖刺激下胰岛素分泌增强，表明ALK7负向调节β细胞中葡萄糖刺激的胰岛素释放。葡萄糖增加了胰岛中ALK7及其配体激活素B的表达，但降低了激活素A的表达，激活素A不通过ALK7信号传导。这两种激活素对胰岛细胞中的Ca(2+)信号传导具有相反的作用，激活素A增加而激活素B减少葡萄糖刺激的Ca(2+)内流。单独作用时，激活素B对野生型细胞无影响，但刺激缺乏ALK7的细胞中的Ca(2+)内流。与此一致的是，缺乏激活素B的突变小鼠表现出与Alk7(-/-)小鼠相当的高胰岛素血症，但双突变体没有叠加效应，表明ALK7和激活素B在调节胰岛素分泌的共同途径中发挥作用。这些发现揭示了激活素A和B在β细胞Ca(2+)信号传导控制中的意外拮抗作用。我们提出，ALK7在调节胰岛的功能可塑性中起重要作用，通过介导激活素B对Ca(2+)信号传导的影响来负向影响β细胞功能。
