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Control of human potassium channel inactivation by editing of a small mRNA hairpin

Nature Structural & Molecular Biology volume 11, pages 950–956 (2004)Cite this article

Abstract

Genomic recoding by A→I RNA editing plays an important role in diversifying the proteins involved in electrical excitability. Here, we describe editing of an intronless potassium channel gene. A small region of human KV1.1 mRNA sequence directs efficient modification of one adenosine by human adenosine deaminase acting on RNA 2 (hADAR2). Mutational analysis shows that this region adopts a hairpin structure. Electrophysiological characterization reveals that the editing event (I/V) profoundly affects channel inactivation conferred by accessory β subunits. Drosophila melanogaster Shaker channels, mimicking this editing event through mutation, exhibit a similar effect. In addition, we demonstrate that mRNAs for the paralogous D. melanogaster Shab potassium channel are edited at the same position by fly ADAR—a clear example of convergent evolution driven by adenosine deamination. These results suggest an ancient and key regulatory role for this residue in KV channels.

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Figure 1: Minimal KV1.1 sequence necessary for editing.
Figure 2: hKV1.1 RNA editing is directed by a small RNA hairpin.
Figure 3: Effect of editing on hKV1.1 function.
Figure 4: Functional effect of mutating equivalent position to hKV1.1 editing site in D. melanogaster Shaker K+ channel.
Figure 5: Convergence of RNA editing in D. melanogaster Shab (KV2).

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Acknowledgements

We thank D. Srikumar for preparing the Shaker I470V mutant and for a steady supply of transfected cells; M. Callahan and M. Caudill for assistance with tissue culture; D. Lazinski for the gift of ADAR1 and ADAR2 expression constructs; and C. Deutsch, L. Jaffe, J. Mindell and K. Swartz for critical reading of the manuscript. We also thank M. O'Connell and L. Keegan for facilitating this collaboration. This work was supported by a grant from the US National Institutes of Health (NIH) to R.R. and funds from the NIH Intramural Research Program to M.H.

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Authors and Affiliations

  1. Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, 06030, Connecticut, USA

    Tarun Bhalla & Robert Reenan

  2. Institute of Neurobiology, University of Puerto Rico-Medical Sciences Campus, San Juan, 00901, Puerto Rico, USA

    Joshua J C Rosenthal

  3. Molecular Neurophysiology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Miguel Holmgren

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  1. Tarun Bhalla
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Correspondence to Miguel Holmgren or Robert Reenan.

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Bhalla, T., Rosenthal, J., Holmgren, M. et al. Control of human potassium channel inactivation by editing of a small mRNA hairpin. Nat Struct Mol Biol 11, 950–956 (2004). https://doi.org/10.1038/nsmb825

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