title: Regulated RNA editing and functional epistasis in Shaker potassium channels.
abstract: 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 2(4) = 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.
authors.affiliation: Department of Molecular Physiology and Biophysics, Institute of Hyperexcitability, Jefferson Medical College, Philadelphia, PA 19107, USA.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Ingleby
authors.forename: Rachel
authors.initials: R
authors.lastname: Maloney
authors.forename: James
authors.initials: J
authors.lastname: Jepson
authors.forename: Richard
authors.initials: R
authors.lastname: Horn
authors.forename: Robert
authors.initials: R
authors.lastname: Reenan
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics* / Q000502:physiology; D004843:Epistasis, Genetic; D008954:Models, Biological; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D017393:RNA Editing / Q000235:genetics*; D051637:Shaker Superfamily of Potassium Channels / Q000235:genetics* / Q000502:physiology
chemical_list: D029721:Drosophila Proteins; D020033:Protein Isoforms; C496929:Sh protein, Drosophila; D051637:Shaker Superfamily of Potassium Channels