Alternative splicing and polyadenylation contribute to the generation of hERG1 C-terminal isoforms

Qiuming Gong, Matthew R. Stump, A. Russell Dunn, Vivianne Deng, Zhengfeng Zhou

    Research output: Contribution to journalArticle

    12 Scopus citations

    Abstract

    The human ether-a-go-go-related gene 1 (hERG1) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel. Several hERG1 isoforms with different N- and C-terminal ends have been identified. The hERG1a, hERG1b, and hERG1-3.1 isoforms contain the full-length C terminus, whereas the hERG1USO isoforms, hERG1aUSO and hERG1b USO, lack most of the C-terminal domain and contain a unique C-terminal end. The mechanisms underlying the generation of hERG1USO isoforms are not understood. We show that hERG1 isoforms with different C-terminal ends are generated by alternative splicing and polyadenylation of hERG1 pre-mRNA. We identified an intrinsically weak, noncanonical poly(A) signal, AGUAAA, within intron 9 of hERG1 that modulates the expression of hERG1a and hERG1aUSO. Replacing AGUAAA with the strong, canonical poly(A) signal AAUAAA resulted in the predominant production of hERG1aUSO and a marked decrease in hERG1 current. In contrast, eliminating the intron 9 poly(A) signal or increasing the strength of 5′ splice site led to the predominant production of hERG1a and a significant increase in hERG1 current. We found significant variation in the relative abundance of hERG1 C-terminal isoforms in different human tissues. Taken together, these findings suggest that post-transcriptional regulation of hERG1 pre-mRNA may represent a novel mechanism to modulate the expression and function of hERG1 channels.

    Original languageEnglish (US)
    Pages (from-to)32233-32241
    Number of pages9
    JournalJournal of Biological Chemistry
    Volume285
    Issue number42
    DOIs
    StatePublished - Oct 15 2010

      Fingerprint

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

    Cite this