Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
Front Neuroendocrinol. 2023 Oct;71:101099. doi: 10.1016/j.yfrne.2023.101099. Epub 2023 Aug 28.
It is well established that retinoic acid receptors (RARs) function as nuclear receptors that control gene expression in response to binding of the ligand retinoic acid (RA). However, some studies have proposed that RAR-alpha (RARa) controls synaptic plasticity via non-genomic effects outside the nucleus, i.e. effects on mRNA translation of GluA1, a sub-unit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. In order to support this non-genomic mechanism, studies have reported RARa knockout mice or treatment with pharmacological levels of RA and RAR antagonists to propose that RARa is required to control normal synaptic plasticity. A major shortcoming of the non-genomic hypothesis is that there have been no mutational studies showing that RARa can bind the GluA1 mRNA to control GLUA1 protein levels in a non-genomic manner. Also, without a genetic study that removes the endogenous ligand RA, it is impossible to conclude that RARa and its ligand RA control synaptic plasticity through a non-genomic signaling mechanism.
已经证实，维甲酸受体（RARs）作为核受体，通过结合配体维甲酸（RA）来控制基因表达。然而，一些研究提出 RAR-α（RARa）通过核外的非基因组效应控制突触可塑性，即对α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体亚基 GluA1 的 mRNA 翻译的影响。为了支持这种非基因组机制，研究已经报道了 RARa 敲除小鼠或用药理学水平的 RA 和 RAR 拮抗剂处理，以提出 RARa 是控制正常突触可塑性所必需的。非基因组假说的一个主要缺点是，没有突变研究表明 RARa 可以结合 GluA1 mRNA 以非基因组方式控制 GLUA1 蛋白水平。此外，在没有去除内源性配体 RA 的遗传研究的情况下，不可能得出结论认为 RARa 和其配体 RA 通过非基因组信号机制控制突触可塑性。
