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cGMP/PKG-I Pathway–Mediated GLUT1/4 Regulation by NO in Female Rat Granulosa Cells

Nitric oxide (NO) is a multifunctional gaseous molecule that plays important roles in mammalian reproductive functions, including follicular growth and development. Although our previous study showed that NO mediated 3,5,3'-triiodothyronine and follicle-stimulating hormone-induced granulosa cell development via upregulation of glucose transporter protein (GLUT)1 and GLUT4 in granulosa cells, little is known about the precise mechanisms regulating ovarian development via glucose. The objective of the present study was to determine the cellular and molecular mechanism by which NO regulates GLUT expression and glucose uptake in granulosa cells. Our results indicated that NO increased GLUT1/GLUT4 expression and translocation in cells, as well as glucose uptake. These changes were accompanied by upregulation of cyclic guanosine monophosphate (cGMP) level and cGMP-dependent protein kinase (PKG)-I protein content. The results of small interfering RNA (siRNA) analysis showed that knockdown of PKG-I significantly attenuated gene expression, translocation, and glucose uptake. Moreover, the PKG-I inhibitor also blocked the above processes. Furthermore, NO induced cyclic adenosine monophosphate response element binding factor (CREB) phosphorylation, and CREB siRNA attenuated NO-induced GLUT expression, translocation, and glucose uptake in granulosa cells. These findings suggest that NO increases cellular glucose uptake via GLUT upregulation and translocation, which are mediated through the activation of the cGMP/PKG pathway. Meanwhile, the activated CREB is also involved in the regulation. These findings indicate that NO has an important influence on the glucose uptake of granulosa cells.