Kimple Michelle E, Joseph Jamie W, Bailey Candice L, Fueger Patrick T, Hendry Ian A, Newgard Christopher B, Casey Patrick J
Department of Pharmacology, and The Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina 27710-3813, USA.
J Biol Chem. 2008 Feb 22;283(8):4560-7. doi: 10.1074/jbc.M706481200. Epub 2007 Dec 20.
Relatively little is known about the in vivo functions of the alpha subunit of the heterotrimeric G protein Gz (Galphaz). Clues to one potential function recently emerged with the finding that activation of Galphaz inhibits glucose-stimulated insulin secretion in an insulinoma cell line (Kimple, M. E., Nixon, A. B., Kelly, P., Bailey, C. L., Young, K. H., Fields, T. A., and Casey, P. J. (2005) J. Biol. Chem. 280, 31708-31713). To extend this study in vivo, a Galphaz knock-out mouse model was utilized to determine whether Galphaz function plays a role in the inhibition of insulin secretion. No differences were discovered in the gross morphology of the pancreatic islets or in the islet DNA, protein, or insulin content between Galphaz-null and wild-type mice. There was also no difference between the insulin sensitivity of Galphaz-null mice and wild-type controls, as measured by insulin tolerance tests. Galphaz-null mice did, however, display increased plasma insulin concentrations and a corresponding increase in glucose clearance following intraperitoneal and oral glucose challenge as compared with wild-type controls. The increased plasma insulin observed in Galphaz-null mice is most likely a direct result of enhanced insulin secretion, since pancreatic islets isolated from Galphaz-null mice exhibited significantly higher glucose-stimulated insulin secretion than those of wild-type mice. Finally, the increased insulin secretion observed in Galphaz-null islets appears to be due to the relief of a tonic inhibition of adenylyl cyclase, as cAMP production was significantly increased in Galphaz-null islets in the absence of exogenous stimulation. These findings indicate that Galphaz may be a potential new target for therapeutics aimed at ameliorating beta-cell dysfunction in Type 2 diabetes.
对于异源三聚体G蛋白Gz（Gαz）的α亚基的体内功能，人们了解相对较少。最近有一项发现为其一种潜在功能提供了线索，即Gαz的激活会抑制胰岛素瘤细胞系中葡萄糖刺激的胰岛素分泌（金普尔，M.E.，尼克松，A.B.，凯利，P.，贝利，C.L.，杨，K.H.，菲尔兹，T.A.，以及凯西，P.J.（2005年）《生物化学杂志》280卷，31708 - 31713页）。为了在体内扩展这项研究，利用了Gαz基因敲除小鼠模型来确定Gαz功能是否在胰岛素分泌抑制中起作用。在Gαz基因缺失小鼠和野生型小鼠之间，胰岛的大体形态、胰岛DNA、蛋白质或胰岛素含量均未发现差异。通过胰岛素耐量试验测量，Gαz基因缺失小鼠和野生型对照的胰岛素敏感性也没有差异。然而，与野生型对照相比，Gαz基因缺失小鼠在腹腔注射和口服葡萄糖刺激后，血浆胰岛素浓度升高，葡萄糖清除率相应增加。在Gαz基因缺失小鼠中观察到的血浆胰岛素升高很可能是胰岛素分泌增强的直接结果，因为从Gαz基因缺失小鼠分离的胰岛比野生型小鼠的胰岛表现出显著更高的葡萄糖刺激的胰岛素分泌。最后，在Gαz基因缺失的胰岛中观察到的胰岛素分泌增加似乎是由于腺苷酸环化酶的紧张性抑制解除，因为在没有外源性刺激的情况下，Gαz基因缺失的胰岛中cAMP产生显著增加。这些发现表明，Gαz可能是旨在改善2型糖尿病β细胞功能障碍的治疗方法的一个潜在新靶点。
