Welden Justin R, Zhang Zhaiyi, Duncan Marilyn J, Falaleeva Marina, Wells Timothy, Stamm Stefan
Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, 40503, United States.
Dept. of Neuroscience, University of Kentucky College of Medicine, Lexington, KY, 40536, United States.
Neurosci Lett. 2018 Sep 25;684:132-139. doi: 10.1016/j.neulet.2018.06.051. Epub 2018 Jun 30.
The serotonin receptor 2C (5HT2C) is an important drug target to treat obesity and depression. Its pre-mRNA undergoes alternative splicing, encoding a short RNA1 isoform that is localized intracellularly and a full-length isoform (RNA2) that can reach the cell membrane. These splicing isoforms are deregulated in Prader-Willi syndrome (PWS), due to the loss of a trans-acting regulatory RNA, SNORD115. Here we show that the 5HT2C mRNA is expressed in the posterior pituitary, suggesting that 5HT2C mRNA is generated in the hypothalamus and subsequently conveyed by axonal transport. In the pituitary, the ratio of 5HT2C isoforms is regulated by feeding, and can be manipulated using a splice-site changing oligonucleotide injected into the blood. The pituitary expression of the 5HT2C mRNA may constitute a previously unknown mechanism whereby serotonin in the circulation or drugs targeting the 5HT2C might induce side-effects. Finally, the deregulation of 5HT2C splicing isoforms in PWS could contribute to the known hormonal imbalances.
血清素受体2C（5HT2C）是治疗肥胖症和抑郁症的重要药物靶点。其前体mRNA经历可变剪接，编码一种定位于细胞内的短RNA1亚型和一种可到达细胞膜的全长亚型（RNA2）。由于反式作用调节RNA SNORD115的缺失，这些剪接亚型在普拉德-威利综合征（PWS）中失调。在这里，我们表明5HT2C mRNA在后叶垂体中表达，这表明5HT2C mRNA在下丘脑产生，随后通过轴突运输传递。在垂体中，5HT2C亚型的比例受进食调节，并且可以通过向血液中注射改变剪接位点的寡核苷酸来操控。5HT2C mRNA在垂体中的表达可能构成一种先前未知的机制，通过该机制，循环中的血清素或靶向5HT2C的药物可能会诱发副作用。最后，PWS中5HT2C剪接亚型的失调可能导致已知的激素失衡。
