Pyrvinium pamoate changes alternative splicing of the serotonin receptor 2C by influencing its RNA structure

Manli Shen, Stanislav Bellaousov, Michael Hiller, Pierre De La Grange, Trevor P. Creamer, Orit Malina, Ruth Sperling, David H. Mathews, Peter Stoilov, Stefan Stamm

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


The serotonin receptor 2C plays a central role in mood and appetite control. It undergoes pre-mRNA editing as well as alternative splicing. The RNA editing suggests that the pre-mRNA forms a stable secondary structure in vivo. To identify substances that promote alternative exons inclusion, we set up a high-throughput screen and identified pyrvinium pamoate as a drug-promoting exon inclusion without editing. Circular dichroism spectroscopy indicates that pyrvinium pamoate binds directly to the pre-mRNA and changes its structure. SHAPE (selective 2′-hydroxyl acylation analysed by primer extension) assays show that part of the regulated 5′-splice site forms intramolecular base pairs that are removed by this structural change, which likely allows splice site recognition and exon inclusion. Genome-wide analyses show that pyrvinium pamoate regulates >300 alternative exons that form secondary structures enriched in A-U base pairs. Our data demonstrate that alternative splicing of structured pre-mRNAs can be regulated by small molecules that directly bind to the RNA, which is reminiscent to an RNA riboswitch.

Original languageEnglish
Pages (from-to)3819-3832
Number of pages14
JournalNucleic Acids Research
Issue number6
StatePublished - Apr 2013

Bibliographical note

Funding Information:
NIH [RO1 GM083187, P20RR020171; R01 GM076485 to D.H.M.]; Foundation for Prader–Willi Research (to S.S.); Binational Science Foundation (BSF), USA-Israel, Transformative Grant [2010508 to S.S. and R.S.]. Funding for open access charge: NIH [RO1 GM083187].

ASJC Scopus subject areas

  • Genetics


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