A mutation in the G-protein-linked inwardly rectifying K(+) channel 2 gene (Girk2) is the cause of the weaver mouse phenotype. We determined that the originally published Girk2 transcript is composed of five exons. The primary coding exon (designated exon 4a in our system) encodes over two- thirds of the protein. Five different full-length Girk2 transcript isoforms (designated Girk2-1, Girk2A-1, Girk2A-2, Girk2B, and Girk2C) originating from different transcriptional start sites and/or alternative splicing were isolated by cDNA RACE. Several of the transcripts were predicted to encode truncated proteins that may lack some of the G-protein coupling sequence. Northern blotting and in situ hybridization studies with transcript-specific probes indicated that the transcripts were differentially expressed in both normal and weaver mice. All transcripts tested were expressed in the three major targets of action of the weaver mutation: cerebellum, substantia nigra, and testis. Two of the transcripts, Girk2A-1 and Girk2A-2, encode identical proteins and have a distinct pattern of expression in testis, which suggests that they are associated with specific stages of spermatogenesis. An additional transcript, Girk2D, appears to be brain-specific, not polyadenylated, and highly expressed in cerebellar granule cells.
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