4 5-HYDROXYTRYPTAMINE(7) (5-HT7) RECEPTOR ISOFORMS IN HUMAN AND RAT PRODUCED BY ALTERNATIVE SPLICING - SPECIES-DIFFERENCES DUE TO ALTERED INTRON-EXON ORGANIZATION

The serotonin (5-HT) 5-HT7 receptor subtype is thought to mediate a nu mber of physiological effects in mammalian brain and periphery. Previo us studies suggested that alternative splicing might contribute to 5-H T7 receptor diversity as well. We now report that alternative splicing in human and rat tissues produces four 5-HT7 receptor isoforms that d iffer in their predicted C-terminal intracellular tails. Human and rat partial 5-HT7 cDNAs and intronic sequences were identified and compar ed. In rat tissues, three 5-HT7 isoforms, here called 5-HT7(a) 5-HT7(b ) and 5-HT7(c), are found. Rat 5-HT7(a) [448-amino acid (aa)] and 5-HT 7(b) (435-aa) forms arise from alternative splice donor sites. A third new isoform found in rat, 5-HT7(c) (470-aa), results from a retained exon cassette. Three 5-HT7 mRNA isoforms were also identified in human tissues, where only one isoform was previously described. Two human i soforms represent 5-HT7(a) and 5-HT7(b) forms (445- and 432-aa), but t he third form does not correspond to 5-HT7(c). Instead, it constitutes a distinct isoform, 5-HT7(d) (479-aa), resulting from retention of a separate exon cassette. 5-HT7(d) transcripts are not present in rat be cause the 5-HT7(d)-specifying exon is absent from the rat 5-HT7 gene. A frame-shifting homologue of the rat 5-HT7(c)-specifying exon is pres ent in the human gene but is not used in the human tissues examined. T issue-specific splicing differences are present in human between brain and spleen. These studies suggest that alternative splicing may contr ibute to diversity of 5-HT7 receptor action and that the human and rat repertoires of 5-HT7 splice variants are substantially different.