The Journal of General Physiology
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Published online
doi:10.1085/jgp.200810133
The Journal of General Physiology, Vol. 133, No. 1, 17-27
The Rockefeller University Press, 0022-1295 $30.00
© Ingleby et al.
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ARTICLE

 Regulated RNA Editing and Functional Epistasis in Shaker Potassium Channels



Lindsey Ingleby1, Rachel Maloney2, James Jepson2, Richard Horn1, and Robert Reenan2

1 Department of Molecular Physiology and Biophysics, Institute of Hyperexcitability, Jefferson Medical College, Philadelphia, PA 19107
2 Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912

Correspondence to Robert Reenan: Robert_Reenan{at}Brown.edu

Regulated point modification by an RNA editing enzyme occurs at four conserved sites in the Drosophila Shaker potassium channel. Single mRNA molecules can potentially represent any of 24 = 16 permutations (isoforms) of these natural variants. We generated isoform expression profiles to assess sexually dimorphic, spatial, and temporal differences. Striking tissue-specific expression was seen for particular isoforms. Moreover, isoform distributions showed evidence for coupling (linkage) of editing sites. Genetic manipulations of editing enzyme activity demonstrated that a chief determinant of Shaker editing site choice resides not in the editing enzyme, but rather, in unknown factors intrinsic to cells. Characterizing the biophysical properties of currents in nine isoforms revealed an unprecedented feature, functional epistasis; biophysical phenotypes of isoforms cannot be explained simply by the consequences of individual editing effects at the four sites. Our results unmask allosteric communication across disparate regions of the channel protein and between evolved and regulated amino acid changes introduced by RNA editing.

L. Ingleby and R. Maloney contributed equally to this work.

Abbreviations used in this paper: ADAR, adenosine deaminase acting on RNA; A-to-I, adenosine-to-inosine; ds, double-stranded; ECS, editing site complementary sequence; RT, reverse transcription.

© 2009 Ingleby et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jgp.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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