胞质腺苷酸激酶调节人β细胞中的K-ATP通道活性。
Cytosolic adenylate kinases regulate K-ATP channel activity in human beta-cells.
作者信息
Stanojevic Violeta, Habener Joel F, Holz George G, Leech Colin A
机构信息
Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
出版信息
Biochem Biophys Res Commun. 2008 Apr 11;368(3):614-9. doi: 10.1016/j.bbrc.2008.01.109. Epub 2008 Feb 1.
Abstract
The role of adenylate kinase (AK) as a determinant of K-ATP channel activity in human pancreatic beta-cells was investigated. We have identified that two cytosolic isoforms of AK, AK1 and AK5 are expressed in human islets and INS-1 cells. Elevated concentrations of glucose inhibit AK1 expression and AK1 immunoprecipitates with the Kir6.2 subunit of K-ATP. AK activation by ATP+AMP stimulates K-ATP channel activity and this stimulation is abolished by AK inhibitors. We propose that glucose stimulation of beta-cells inhibits AK through glycolysis and also through the elevation of diadenosine polyphosphate levels. Glucose-dependent inhibition of AK increases the ATP/ADP ratio in the microenvironment of the K-ATP channel promoting channel closure and insulin secretion. The down-regulation of AK1 expression by hyperglycemia may contribute to the defective coupling of glucose metabolism to K-ATP channel activity in type 2 diabetes.
摘要
研究了腺苷酸激酶（AK）作为人类胰腺β细胞中K-ATP通道活性决定因素的作用。我们已经确定，AK的两种胞质异构体AK1和AK5在人类胰岛和INS-1细胞中表达。高浓度葡萄糖会抑制AK1的表达，并且AK1会与K-ATP的Kir6.2亚基进行免疫沉淀。ATP+AMP对AK的激活会刺激K-ATP通道活性，而这种刺激会被AK抑制剂消除。我们提出，β细胞的葡萄糖刺激通过糖酵解以及通过增加二腺苷多磷酸水平来抑制AK。葡萄糖依赖性的AK抑制会增加K-ATP通道微环境中的ATP/ADP比值，从而促进通道关闭和胰岛素分泌。高血糖对AK1表达的下调可能导致2型糖尿病中葡萄糖代谢与K-ATP通道活性的缺陷偶联。
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