Pasula Madhu Babu, Sylvester Paul W, Briski Karen P
School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA 71201, USA.
IBRO Neurosci Rep. 2024 May 22;16:635-642. doi: 10.1016/j.ibneur.2024.05.008. eCollection 2024 Jun.
Recent studies documented regulation of hypothalamic astrocyte mitogen-activated protein kinase (MAPK) pathways, including p38, by the plasma membrane glucose carrier/sensor glucose transporter-2 (GLUT2). Sex-specific GLUT2 control of p38 phosphorylation was observed, but effects on individual p38 family protein profiles were not investigated. Current research employed an established primary astrocyte culture model, gene knockdown tools, and selective primary antisera against p38-alpha, p38-beta, p38-gamma, and p38-delta isoforms to investigate whether GLUT2 governs expression of one or more of these variants in a glucose-dependent manner. Data show that GLUT2 inhibits baseline expression of each p38 protein in male cultures, yet stimulates p38-delta profiles without affecting other p38 proteins in female. Glucose starvation caused selective up-regulation of p38-delta profiles in male versus p38-alpha and -gamma proteins in female; these positive responses were amplified by GLUT2 siRNA pretreatment. GLUT2 opposes or enhances basal p38 phosphorylation in male versus female, respectively. GLUT2 siRNA pretreatment did not affect glucoprivic patterns of phospho-p38 protein expression in either sex. Outcomes document co-expression of the four principal p38 MAPK family proteins in hypothalamic astrocytes, and implicate GLUT2 in regulation of all (male) versus one (female) variant(s). Glucoprivation up-regulated expression of distinctive p38 isoforms in each sex; these stimulatory responses are evidently blunted by GLUT2. Glucoprivic-associated loss of GLUT2 gene silencing effects on p38 phosphorylation infers either that glucose status determines whether this sensor controls phosphorylation, or that decrements in screened glucose in each instance are of sufficient magnitude to abolish GLUT2 regulation of that function.
近期研究记录了质膜葡萄糖载体/传感器葡萄糖转运蛋白2（GLUT2）对下丘脑星形胶质细胞丝裂原活化蛋白激酶（MAPK）途径（包括p38）的调节作用。观察到GLUT2对p38磷酸化存在性别特异性控制，但未研究其对单个p38家族蛋白谱的影响。当前研究采用已建立的原代星形胶质细胞培养模型、基因敲低工具以及针对p38-α、p38-β、p38-γ和p38-δ亚型的选择性原代抗血清，以研究GLUT2是否以葡萄糖依赖的方式调控这些变体中的一种或多种的表达。数据表明，GLUT2抑制雄性培养物中各p38蛋白的基础表达，但在雌性中刺激p38-δ蛋白谱而不影响其他p38蛋白。葡萄糖饥饿导致雄性中p38-δ蛋白谱选择性上调，而雌性中p38-α和 -γ蛋白上调；这些阳性反应通过GLUT2 siRNA预处理得到增强。GLUT2分别在雄性和雌性中对抗或增强基础p38磷酸化。GLUT2 siRNA预处理对两性中磷酸化p38蛋白表达的糖缺乏模式均无影响。结果证明下丘脑星形胶质细胞中四种主要p38 MAPK家族蛋白共表达，并表明GLUT2参与调控所有（雄性）或一种（雌性）变体。糖缺乏上调了两性中不同p38亚型的表达；这些刺激反应显然被GLUT2减弱。糖缺乏相关的GLUT2基因沉默对p38磷酸化的影响丧失，意味着要么葡萄糖状态决定该传感器是否控制磷酸化，要么在每种情况下筛选的葡萄糖减少幅度足以消除GLUT2对该功能的调节。
