Fricke Steffen, Harnau Magnus, Hetsch Florian, Liu Haoran, Leonhard Julia, Eylmann Anna, Knauff Pina, Sun Han, Semtner Marcus, Meier Jochen C
Division Cell Physiology, Zoological Institute, Technische Universität Braunschweig, Braunschweig, Germany.
Institute of Pathophysiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Front Mol Neurosci. 2023 May 22;16:1018530. doi: 10.3389/fnmol.2023.1018530. eCollection 2023.
The monovalent cations sodium and potassium are crucial for the proper functioning of excitable cells, but, in addition, other monovalent alkali metal ions such as cesium and lithium can also affect neuronal physiology. For instance, there have been recent reports of adverse effects resulting from self-administered high concentrations of cesium in disease conditions, prompting the Food and Drug Administration (FDA) to issue an alert concerning cesium chloride. As we recently found that the monovalent cation NH activates glycine receptors (GlyRs), we investigated the effects of alkali metal ions on the function of the GlyR, which belongs to one of the most widely distributed neurotransmitter receptors in the peripheral and central nervous systems. Whole-cell voltage clamp electrophysiology was performed with HEK293T cells transiently expressing different splice and RNA-edited variants of GlyR α2 and α3 homopentameric channels. By examining the influence of various milli- and sub-millimolar concentrations of lithium, sodium, potassium, and cesium on these GlyRs in comparison to its natural ligand glycine (0.1 mM), we could show that cesium activates GlyRs in a concentration- and post-transcriptional-dependent way. Additionally, we conducted atomistic molecular dynamic simulations on GlyR α3 embedded in a membrane bilayer with potassium and cesium, respectively. The simulations revealed slightly different GlyR-ion binding profiles for potassium and cesium, identifying interactions near the glycine binding pocket (potassium and cesium) and close to the RNA-edited site (cesium) in the extracellular GlyR domain. Together, these findings show that cesium acts as an agonist of GlyRs.
单价阳离子钠和钾对于可兴奋细胞的正常功能至关重要，但除此之外，其他单价碱金属离子如铯和锂也会影响神经元生理。例如，最近有报道称，在疾病状态下自行服用高浓度铯会产生不良影响，促使美国食品药品监督管理局（FDA）发布了关于氯化铯的警报。由于我们最近发现单价阳离子NH可激活甘氨酸受体（GlyRs），因此我们研究了碱金属离子对GlyR功能的影响，GlyR是外周和中枢神经系统中分布最广泛的神经递质受体之一。利用瞬时表达GlyR α2和α3同五聚体通道不同剪接和RNA编辑变体的HEK293T细胞进行全细胞膜片钳电生理学研究。通过检测各种毫摩尔和亚毫摩尔浓度的锂、钠、钾和铯与其天然配体甘氨酸（0.1 mM）相比对这些GlyRs的影响，我们发现铯以浓度和转录后依赖性方式激活GlyRs。此外，我们分别对嵌入膜双层中的GlyR α3与钾和铯进行了原子分子动力学模拟。模拟结果揭示了钾和铯与GlyRs的离子结合模式略有不同，确定了在细胞外GlyR结构域中甘氨酸结合口袋附近（钾和铯）以及靠近RNA编辑位点（铯）的相互作用。这些发现共同表明铯可作为GlyRs的激动剂。
