Pasula MadhuBabu, Roy Sagor C, Bheemanapally Khaggeswar, Sylvester Paul W, Briski Karen P
School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA 71201.
Neuroglia. 2023 Sep;4(3):158-171. doi: 10.3390/neuroglia4030011. Epub 2023 Jun 21.
The plasma membrane glucose transporter (GLUT)-2 is unique among GLUT family proteins in that it also functions as a glucose sensor. GLUT2 imposes sex-dimorphic control of hypothalamic astrocyte glucose storage and catabolism by unknown mechanisms. Mitogen-activated protein kinase (MAPK) signaling cascades operate within stress-sensitive signal transduction pathways. Current research employed an established primary astrocyte culture model and gene knockdown tools to investigate whether one or more of the three primary MAP kinase families are regulated by GLUT2. GLUT2 gene knockdown caused opposing adjustments in total ERK1/2 proteins in glucose-supplied male versus female astrocytes, augmenting or reducing the mean phosphorylated/total protein ratio for 44 and 42 kDa variants in these sexes. Glucose deprivation amplified this ratio for both ERK1/2 variants, albeit by a larger magnitude in male; GLUT2 siRNA exacerbated this stimulatory response in males only. Phosphorylated/total p38 MAPK protein ratios were up-regulated by GLUT2 knockdown in male, but not female astrocytes. Glucose-deprived astrocytes exhibited no change (male) or reduction (female) in this ratio after GLUT2 gene silencing. GLUT2 siRNA increased the phosphorylated/total protein ratio for 54 and 46 kDa SAPK/JNK proteins in each sex when glucose was present. However, glucose withdrawal suppressed (male) or amplified (female) these ratios, while GLUT2 knockdown attenuated these inverse responses. Results show that GLUT2 inhibits ERK1/2, p38, and SAPK/JNK MAPK activity in male, but differentially stimulates and inhibits activity of these signaling pathways in female hypothalamic astrocytes. Glucoprivation induces divergent adjustments in astrocyte p38 MAPK and SAPK/JNK activities. The findings demonstrate a stimulatory role for GLUT2 in p38 MAPK activation in glucose-starved female astrocytes, but can act as either an inhibitor or inducer of SAPK/JNK activation in glucose-deprived male versus female glial cells, respectively.
质膜葡萄糖转运蛋白（GLUT）-2在GLUT家族蛋白中独具特色，因为它还起着葡萄糖传感器的作用。GLUT2通过未知机制对下丘脑星形胶质细胞的葡萄糖储存和分解代谢施加性别二态性控制。丝裂原活化蛋白激酶（MAPK）信号级联在应激敏感信号转导途径中发挥作用。当前的研究采用了已建立的原代星形胶质细胞培养模型和基因敲低工具，以研究三个主要MAP激酶家族中的一个或多个是否受GLUT2调控。GLUT2基因敲低导致在葡萄糖供应的雄性和雌性星形胶质细胞中总ERK1/2蛋白出现相反的调节，增加或降低了这些性别中44 kDa和42 kDa变体的平均磷酸化/总蛋白比率。葡萄糖剥夺使两种ERK1/2变体的这一比率均升高，尽管在雄性中升高幅度更大；GLUT2 siRNA仅在雄性中加剧了这种刺激反应。在雄性而非雌性星形胶质细胞中，GLUT2敲低使磷酸化/总p-38 MAPK蛋白比率上调。GLUT2基因沉默后，葡萄糖剥夺的星形胶质细胞在该比率上无变化（雄性）或降低（雌性）。当存在葡萄糖时，GLUT2 siRNA增加了两性中54 kDa和46 kDa SAPK/JNK蛋白的磷酸化/总蛋白比率。然而，葡萄糖撤除抑制（雄性）或放大（雌性）了这些比率，而GLUT2敲低减弱了这些相反的反应。结果表明，GLUT2在雄性中抑制ERK1/2、p38和SAPK/JNK MAPK活性，但在雌性下丘脑星形胶质细胞中对这些信号通路的活性有不同的刺激和抑制作用。葡萄糖缺乏诱导星形胶质细胞p38 MAPK和SAPK/JNK活性发生不同的调节。这些发现证明了GLUT2在葡萄糖饥饿的雌性星形胶质细胞中对p38 MAPK激活具有刺激作用，但在葡萄糖剥夺的雄性和雌性神经胶质细胞中，它分别可以作为SAPK/JNK激活的抑制剂或诱导剂。
