The genomic basis of K(V)3.4 potassium channel mRNA diversity in mice

K(v)3.4 belongs to the shaw subfamily of shaker-type potassium channels. It conducts fast inactivating, high threshold currents in the central nervous system and in fast-twitch skeletal muscle fibers. The corresponding mouse gene, Kcnc4, consists of five exons spanning a region of 20 kb. Approximate ly 700 bp of regulatory sequence were delineated. It is GC rich and lacks t ypical TATA and CAAT motifs. Instead, seven Sp-1 and three E-box elements d efine putative regulatory sequences. The mouse K(v)3.4 mRNA has a size of 3 639 bp, 1120 bp of which are 3' untranslated region. A transcript initiated from an alternative 5'-exon was identified by RACE and verified by genomic analysis. This isoform, designated K(v)3.4d, is predominantly expressed in skeletal muscle and probably results from alternative promoter usage. It e ncodes a channel protein with a novel N-terminal cytoplasmic domain. It lac ks the conserved sequence motifs encoding the shaw-type tetramerization dom ain and the 'ball' peptide, which confers fast inactivation properties. Ano ther splice variant, K(v)3.4c, is derived by exon skipping in the C-termina l region and is expressed at similar levels in brain and muscle. These data demonstrate that differential splicing and alternative transcription start sites are utilised to generate a set of K(v)3.4 variants in skeletal muscl e and brain, presumably involved in the regulation of excitability. (C) 200 1 Elsevier Science B.V. All rights reserved.