Department of Physiology, Georgia Health Sciences University, Augusta, 30912, USA.
Am J Physiol Regul Integr Comp Physiol. 2012 Aug 1;303(3):R291-300. doi: 10.1152/ajpregu.00056.2012. Epub 2012 Jun 13.
Neurohumoral activation, which includes augmented plasma levels of the neurohormone vasopressin (VP), is a common finding in heart failure (HF) that contributes to morbidity and mortality in this disease. While an increased activation of magnocellular neurosecretory cells (MNCs) and enhanced glutamate function in HF is well documented, the precise underlying mechanisms remain to be elucidated. Here, we combined electrophysiology and protein measurements to determine whether altered glial glutamate transporter function and/or expression occurs in the hypothalamic supraoptic nucleus (SON) during HF. Patch-clamp recordings obtained from MNCs in brain slices show that pharmacological blockade of astrocyte glutamate transporter 1 (GLT1) function [500 μM dihydrokainate (DHK)], resulted in a persistent N-methyl-D-aspartate receptor (NMDAR)-mediated inward current (tonic I(NMDA)) in sham rats, an effect that was significantly smaller in MNCs from HF rats. In addition, we found a diminished GLT1 protein content in plasma membrane (but not cytosolic) fractions of SON punches in HF rats. Conversely, astrocyte GLAST expression was significantly higher in the SON of HF rats, while nonselective blockade of glutamate transport activity (100 μM TBOA) evoked an enhanced tonic I(NMDA) activation in HF rats. Steady-state activation of NMDARs by extracellular glutamate levels was diminished during HF. Taken together, these results support a shift in the relative expression and function of two major glial glutamate transporters (from GLT1 to GLAST predominance) during HF. This shift may act as a compensatory mechanism to preserve an adequate basal glutamate uptake level in the face of an enhanced glutamatergic afferent activity in HF rats.
神经体液激活，包括神经激素血管加压素（VP）的血浆水平升高，是心力衰竭（HF）的常见发现，导致这种疾病的发病率和死亡率增加。虽然 HF 中大细胞神经分泌细胞（MNC）的激活增加和谷氨酸功能增强已得到充分证实，但确切的潜在机制仍有待阐明。在这里，我们结合电生理学和蛋白质测量来确定在 HF 期间下丘脑视上核（SON）中是否发生了改变的胶质细胞谷氨酸转运体功能和/或表达。从脑切片中的 MNC 获得的膜片钳记录显示，星形胶质细胞谷氨酸转运体 1（GLT1）功能的药理学阻断[500μM 二氢酮酸（DHK）]导致 Sham 大鼠中持续存在 N-甲基-D-天冬氨酸受体（NMDAR）介导的内向电流（tonic I（NMDA）），而 HF 大鼠中的这种作用明显较小。此外，我们发现 HF 大鼠的 SON 中的 GLT1 蛋白含量在质膜（而非胞质）部分减少。相反，HF 大鼠 SON 中的星形胶质细胞 GLAST 表达显着增加，而谷氨酸转运活性的非选择性阻断（100μM TBOA）在 HF 大鼠中引起增强的 tonic I（NMDA）激活。HF 期间，细胞外谷氨酸水平对 NMDAR 的稳态激活减少。总之，这些结果支持在 HF 期间两种主要胶质细胞谷氨酸转运体（从 GLT1 向 GLAST 优势的相对表达和功能转变）。这种转变可能是一种代偿机制，以在 HF 大鼠增强的谷氨酸能传入活动的情况下保持足够的基础谷氨酸摄取水平。
