We report the isolation of a novel mouse voltage-gated Shaker-related K ؉ channel gene, Kv1.7 (Kcna7/KCNA7). Unlike other known Kv1 family genes that have intronless coding regions, the protein-coding region of Kv1.7 is interrupted by a 1.9-kilobase pair intron. The Kv1.7 gene and the related Kv3.3 (Kcnc3/KCNC3) gene map to mouse chromosome 7 and human chromosome 19q13.3, a region that has been suggested to contain a diabetic susceptibility locus. The mouse Kv1.7 channel is voltage-dependent and rapidly inactivating, exhibits cumulative inactivation, and has a single channel conductance of 21 pS. It is potently blocked by noxiustoxin and stichodactylatoxin, and is insensitive to tetraethylammonium, kaliotoxin, and charybdotoxin. Northern blot analysis reveals ϳ3-kilobase pair Kv1.7 transcripts in mouse heart and skeletal muscle. In situ hybridization demonstrates the presence of Kv1.7 in mouse pancreatic islet cells. Kv1.7 was also isolated from mouse brain and hamster insulinoma cells by polymerase chain reaction.Ion channels that exhibit a variety of gating patterns and ion selectivity are critical elements that transduce signals in diverse cell types (1). Voltage-gated potassium-selective (Kv) 1 channels represent the largest family within this class of proteins (2), and perform many vital functions in both electrically excitable and nonexcitable cells. Following initiation of an action potential in nerve and muscle cells, Kv channels play the important role of repolarizing the cell membrane (1). Kv channels can also modulate hormone secretion, for example insulin release from pancreatic islet cells (3-6), and regulate calcium signaling during mitogen-stimulated activation of lymphocytes (7).Kv channels in mammalian cells are encoded by an extended family of at least nineteen genes (2). The largest subfamily, Kv1, is related to the fly Shaker gene and contains six members, Kv1.1-Kv1.6 (2). The Shaker gene has 21 exons, which can be alternatively spliced to generate at least five functionally distinct transcripts (8, 9). In contrast, the protein-coding regions of each of the six known mammalian Kv1 genes and the three known Xenopus homologues are contained in a single exon (2, 10), precluding alternative splicing as a means of generating functionally different proteins. The evolutionary significance of this pattern of organization remains a puzzle.Here we report the identification of a novel mammalian gene, Kv1.7 (Kcna7/KCNA7), that has a genomic organization distinct from the other members of the vertebrate Kv1 subfamily. We have defined the chromosomal location of this gene in the mouse and human genome, determined its tissue distribution, and characterized the biophysical and pharmacological properties of the cloned channel. mKv1.7, hKv1.7, hKv3.3, and hKv3.4 DNA Clones-Three overlapping genomic clones (KC225, KC254, and KC256) were isolated from an AKR/J mouse genomic library screened with a mixture of mKv1.1 and rKv1.5 cDNA probes, as described previously (10), and mapped by multiple and partial restrict...