Channels get in an HUFA: RNA editing gets them out of a jam.

The enzymatic conversion of adenosine-to-inosine (A-to-I) in RNA rewrites the informational output of a number of different classes of coding and non-coding RNA transcripts. In this issue, Decher et al (2010) reveal a new functional consequence for an ancient RNA editing site in certain animal voltage-gated K channel (Kv) genes. Abundant highly unsaturated fatty acids (HUFAs), which are essential in mammals for normal brain function, block conduction of Kv channels—an effect that can be nearly obliterated by the recoding of a single amino acid through RNA editing. The central dogma of molecular biology elaborates a simple scheme for information flow that has had every biology major reciting the mantra, ‘DNA goes to RNA goes to protein’, for 40 years. Enter the rather byzantine process of RNA editing, which alters an RNA copy post-transcriptionally, rewriting archival genomic information. Achieving this subterfuge requires a diversity of mechanisms, among which is modification of mRNA by the adenosine deaminases acting on RNA (ADAR), which perform a simple hydrolytic deamination on adenosine residues converting them to inosine (Farajollahi and Maas, 2010). Numerous targets have been identified in mRNAs encoding proteins involved in rapid electrical and chemical neurotransmission. In these targets, complex and imperfect short dsRNA structures direct ADAR with exquisite specificity to modify only certain coding positions. As inosine is translated as guanosine by the ribosome, such modification can lead to alteration of amino acid coding positions. One class of targets for ADAR-mediated RNA editing of particular importance are the voltage-gated ion channels (VGICs) genes, where transcripts encoding Na , Ca and K selective channels have all turned up as ADAR substrates in one organism or another. In most cases, the functional consequence of VGIC editing is unknown. However, Decher et al (2010) in this issue of The EMBO Journal reveal a novel role for environment/metabolism to intersect the biological function of an RNA editing site in the potassium channel, Kv1.1. The focus of their studies involves a particular editing event in the Kv1.1 transcript that converts isoleucine-to-valine (I400V). Intriguingly, editing at this exact position has independently evolved by convergence at the homologous position at least three times to enact the same I-to-V change in Kv1 and Kv2 gene families in chordates, mollusks and arthropods. Earlier work demonstrated that the I400V recoding event leads to profound changes in the inactivation properties of the mammalian Kv1.1 and Drosophila Shaker potassium channels in the presence of a protein inactivation ‘ball’, consisting of the extended N-terminus of the channel itself or an accessory b subunit (Bhalla et al, 2004). This cytoplasmic ball ‘snakes’ into the vestibule of an open channel and apparently interacts with the I400 position, thus plugging the pore (Zhou et al, 2001). Editing dramatically destabilizes this interaction, leaving a channel energetically eager to escape the inactivated state. Here, Decher et al (2010) show that HUFAs also seem to act as soluble inactivation balls, binding to the I400 side chain in Kv1.1 (Figure 1). Moreover, the