Dept Translational Neuroscience, University Medical Center Utrecht, Utrecht University, the Netherlands.
Dept Translational Neuroscience, University Medical Center Utrecht, Utrecht University, the Netherlands.
Mol Cell Endocrinol. 2022 Feb 5;541:111501. doi: 10.1016/j.mce.2021.111501. Epub 2021 Nov 2.
Corticosteroid receptors in the mammalian brain mediate genomic as well as non-genomic actions. Although receptors mediating genomic actions were already cloned 35 years ago, it remains unclear whether the same molecules are responsible for the non-genomic actions or that the latter involve a separate class of receptors. Here we focus on one type of corticosteroid receptors, i.e. the mineralocorticoid receptor (MR). We summarize some of the known properties and the current insight in the localization of the MR in peripheral cells and neurons, especially in relation to non-genomic signaling. Previous studies from our own and other labs provided evidence that MRs mediating non-genomic actions are identical to the ones involved in genomic signaling, but may be translocated to the plasma cell membrane instead of the nucleus. With fixed cell imaging and live cell imaging techniques we tried to visualize these presumed membrane-associated MRs, using antibodies or overexpression of MR-GFP in COS7 and hippocampal cultured neurons. Despite the physiological evidence for MR location in or close to the cell membrane, we could not convincingly visualize membrane localization of endogenous MRs or GFP-MR molecules. However, we did find punctae of labeled antibodies intracellularly, which might indicate transactivating spots of MR near the membrane. We also found some evidence for trafficking of MR via beta-arrestins. In beta-arrestin knockout mice, we didn't observe metaplasticity in the basolateral amygdala anymore, indicating that internalization of MRs could play a role during corticosterone activation. Furthermore, we speculate that membrane-associated MRs could act indirectly via activating other membrane located structures like e.g. GPER and/or receptor tyrosine kinases.
哺乳动物大脑中的皮质甾类激素受体介导基因和非基因作用。尽管介导基因作用的受体在 35 年前已经被克隆，但仍不清楚是否相同的分子负责非基因作用，或者后者涉及另一类受体。在这里，我们关注的是一种皮质甾类激素受体，即盐皮质激素受体 (MR)。我们总结了一些已知的性质和目前关于 MR 在周围细胞和神经元中的定位的见解，特别是与非基因信号有关的。我们和其他实验室的先前研究提供了证据，表明介导非基因作用的 MR 与参与基因信号的 MR 相同，但可能被转位到质膜而不是核。我们使用抗体制备或 MR-GFP 在 COS7 和海马培养神经元中的过表达，使用固定细胞成像和活细胞成像技术来尝试可视化这些假定的膜相关 MR。尽管有关于 MR 在质膜内或附近定位的生理证据，但我们无法令人信服地可视化内源性 MR 或 GFP-MR 分子的膜定位。然而，我们确实在细胞内发现了标记抗体的斑点，这可能表明 MR 靠近质膜的转录激活点。我们还发现了一些关于 MR 通过β-arrestin 易位的证据。在β-arrestin 敲除小鼠中，我们不再观察到基底外侧杏仁核的代谢性可塑性，这表明 MR 的内化在皮质酮激活期间可能发挥作用。此外，我们推测膜相关的 MR 可以通过激活其他位于膜上的结构（例如 GPER 和/或受体酪氨酸激酶）间接发挥作用。
