Alternative Splicing and Polyadenylation Contribute to the Generation of hERG1 C-terminal Isoforms

Authors

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

Document Type

Article

Publication Date

2010

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 hERG1_USOisoforms, hERG1a_USO and hERG1b_USO, lack most of the C-terminal domain and contain a unique C-terminal end. The mechanisms underlying the generation of hERG1_USOisoforms 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 hERG1a_USO. Replacing AGUAAA with the strong, canonical poly(A) signal AAUAAA resulted in the predominant production of hERG1a_USO 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.

Comments

Originally published in The Journal of Biological Chemistry. 2010; 285(42):32233-41.

doi: 10.1074/jbc.M109.095695

Recommended Citation

Gong, Qiuming; Stump, Matthew R.; Dunn, A. Russell; Deng, Vivianne; and Zhou, Zhengfeng, "Alternative Splicing and Polyadenylation Contribute to the Generation of hERG1 C-terminal Isoforms" (2010). Faculty Publications - Department of Biological & Molecular Science. 119.
https://digitalcommons.georgefox.edu/bio_fac/119