RNA Editing Generates Tissue-specific Sodium Channels with Distinct Gating Properties

Sodium channels play an essential role in generating the action potential in eukaryotic cells, and their transcripts, especially those in insects, undergo extensive A-to-I RNA editing. The functional consequences of RNA editing of sodium channel transcripts, however, have yet to be determined. We characterized 20 splice variants of the German cockroach sodium channel gene BgNa(v). Functional analysis revealed that these variants exhibited a broad range of voltage-dependent activation and inactivation. Further analysis of two variants, BgNa(v)1-1 and BgNa(v)1-2, which activate at more depolarizing membrane potentials than other variants, showed that RNA editing events were responsible for variant-specific gating properties. Two U-to-C editing sites identified in BgNa(v)1-1 resulted in a Leu to Pro change in segment 1 of domain III (IIIS1) and a Val to Ala change in IVS4. The Leu to Pro change shifted both the voltage dependence of activation and steady-state inactivation in the depolarizing direction. Two A-to-I editing events in BgNa(v)1-2 resulted in a Lys to Arg change in IS2 and an Ile to Met change in IVS3. The Lys to Arg change shifted the voltage dependence of activation in the depolarizing direction. Moreover, these RNA editing events occurred in a tissue-specific and development-specific manner. Our findings provide direct evidence that RNA editing is an important mechanism generating tissue-/cell type-specific functional variants of sodium channels.