Department of Psychiatry, Weill Cornell Medical College, New York, NY 10065, USA.
Proc Natl Acad Sci U S A. 2013 Jul 9;110(28):11624-9. doi: 10.1073/pnas.1301485110. Epub 2013 Jun 24.
The serotonin transporter (SERT) is a major regulator of serotonergic neurotransmission and anxiety-related behaviors. SERT is expressed in two alternative polyadenylation forms that differ by an evolutionarily conserved element in the 3' untranslated region of its mRNA. Expression of SERT mRNA containing the distal polyadenylation element is associated with decreased anxiety-related behaviors in mice and humans, suggesting that this element has behaviorally relevant modulatory effects on SERT expression. We have identified heterogeneous nuclear ribonucleoprotein K (hnRNPK), a protein known to integrate multiple signal transduction pathways with gene expression, as a SERT distal polyadenylation element binding protein. This interaction is functionally meaningful because genetic manipulation of hnRNPK alters expression of the SERT protein. Furthermore, the trophic factor S100β induces Src-family kinase-mediated tyrosine phosphorylation of hnRNPK and increased SERT expression. These results identify a previously unknown mechanism of regulated SERT expression and provide a putative mechanism by which the SERT distal polyadenylation element modulates anxiety-related behaviors.
5-羟色胺转运体（SERT）是 5-羟色胺能神经传递和焦虑相关行为的主要调节剂。SERT 以两种不同的多聚腺苷酸化形式表达，其差异在于 mRNA 的 3'非翻译区中一个进化上保守的元件。含有远端多聚腺苷酸化元件的 SERT mRNA 的表达与小鼠和人类焦虑相关行为的减少有关，这表明该元件对 SERT 表达具有具有行为相关的调节作用。我们已经确定异质核核糖核蛋白 K（hnRNPK）是一种已知的能够将多个信号转导途径与基因表达整合在一起的蛋白质，是 SERT 远端多聚腺苷酸化元件结合蛋白。这种相互作用具有功能意义，因为 hnRNPK 的遗传操作改变了 SERT 蛋白的表达。此外，营养因子 S100β 诱导 Src 家族激酶介导的 hnRNPK 酪氨酸磷酸化和 SERT 表达增加。这些结果确定了调节 SERT 表达的先前未知机制，并提供了 SERT 远端多聚腺苷酸化元件调节焦虑相关行为的潜在机制。
