School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, Louisiana, USA.
Neuroendocrinology. 2024;114(1):25-41. doi: 10.1159/000533627. Epub 2023 Sep 12.
The ventromedial hypothalamic nucleus (VMN) is an estrogen receptor (ER)-rich structure that regulates glucostasis. The role of nuclear but not membrane G protein-coupled ER-1 (GPER) in that function has been studied.
Gene silencing and laser-catapult microdissection/immunoblot tools were used to examine whether GPER regulates transmitter and energy sensor function in dorsomedial (VMNdm) and/or ventrolateral (VMNvl) VMN counter-regulatory nitrergic and γ-Aminobutyric acid (GABA) neurons.
Intra-VMN GPER siRNA administration to euglycemic animals did not affect VMNdm or -vl nitrergic neuron nitric oxide synthase (nNOS), but upregulated (VMNdm) or lacked influence on (VMNvl) GABA nerve cell glutamate decarboxylase65/67 (GAD) protein. Insulin-induced hypoglycemia (IIH) caused GPER knockdown-reversible augmentation of nNOS, 5'-AMP-activated protein kinase (AMPK), and phospho-AMPK proteins in nitrergic neurons in both divisions. IIH had dissimilar effects on VMNvl (unchanged) versus VMNdm (increased) GABAergic neuron GAD levels, yet GPER knockdown affected these profiles. GPER siRNA prevented hypoglycemic upregulation of VMNvl and -dm GABA neuron AMPK without altering pAMPK expression.
Outcomes infer that GPER exerts differential control of VMNdm versus -vl GABA transmission during glucostasis and is required for hypoglycemic upregulated nitrergic (VMNdm and -vl) and GABA (VMNdm) signaling. Glycogen metabolism is reported to regulate VMN nNOS and GAD proteins. Data show that GPER limits VMNvl glycogen phosphorylase (GP) protein expression and glycogen buildup during euglycemia but mediates hypoglycemic augmentation of VMNvl GP protein and glycogen content; VMNdm glycogen mass is refractory to GPER control. GPER regulation of VMNvl glycogen metabolism infers that this receptor may govern local counter-regulatory transmission in part by astrocyte metabolic coupling.
腹内侧下丘脑核（VMN）是富含雌激素受体（ER）的结构，可调节葡萄糖稳态。已经研究了核而非膜 G 蛋白偶联 ER-1（GPER）在该功能中的作用。
使用基因沉默和激光弹射显微解剖/免疫印迹工具，研究 GPER 是否调节背内侧（VMNdm）和/或腹外侧（VMNvl）VMN 抗调节性硝化能和γ-氨基丁酸（GABA）神经元中的递质和能量传感器功能。
向血糖正常的动物的 VMN 内给予 GPER siRNA 注射不会影响 VMNdm 或 -vl 硝化能神经元一氧化氮合酶（nNOS），但会上调（VMNdm）或缺乏对（VMNvl）GABA 神经细胞谷氨酸脱羧酶 65/67（GAD）蛋白的影响。胰岛素诱导的低血糖（IIH）导致硝化能神经元中 nNOS、5'-AMP 激活的蛋白激酶（AMPK）和磷酸化-AMPK 蛋白的 GPER 敲低可逆转增加。IIH 对 VMNvl（未改变）与 VMNdm（增加）GABA 能神经元 GAD 水平有不同的影响，但 GPER 敲低影响这些谱。GPER siRNA 阻止低血糖时 VMNvl 和 -dm GABA 神经元 AMPK 的上调，而不改变 pAMPK 表达。
结果推断，GPER 在葡萄糖稳态期间对 VMNdm 与 -vl GABA 传递发挥不同的控制作用，并且是低血糖时硝化能（VMNdm 和 -vl）和 GABA（VMNdm）信号上调所必需的。据报道，糖原代谢调节 VMN nNOS 和 GAD 蛋白。数据表明，GPER 在血糖正常时限制 VMNvl 糖原磷酸化酶（GP）蛋白表达和糖原积累，但介导 VMNvl GP 蛋白和糖原含量的低血糖增加；VMNdm 糖原质量不受 GPER 控制。GPER 对 VMNvl 糖原代谢的调节表明，该受体可能通过星形胶质细胞代谢偶联部分调节局部抗调节性传递。
