THE 5-HT4 RECEPTOR - MOLECULAR-CLONING AND PHARMACOLOGICAL CHARACTERIZATION OF 2 SPLICE VARIANTS

Molecular cloning efforts have provided primary amino acid sequence an d signal transduction data for a large collection of serotonin recepto r subtypes, These include five 5-HT1-like receptors, three 5-HT2 recep tors, one 5-HT3 receptor, two 5-HT5 receptors, one 5-HT6 receptor and one 5-HT7 receptor, Molecular biological information on the 5-HT4 rece ptor is notably absent from this list, We now report the cloning of th e pharmacologically defined 5-HT4 receptor, Using degenerate oligonucl eotide primers, we identified a rat brain PCR fragment which encoded a '5-HT receptor-like' amino acid sequence, The corresponding full leng th cDNA was isolated from a rat brain cDNA library, Transiently expres sed in COS-7 cells, this receptor stimulates adenylyl cyclase activity and is sensitive to the benzamide derivative cisapride, The response is also blocked by ICS-205930. Interestingly, we isolated two splice v ariants of the receptor, 5-HT4L and 5-HT4S, differing in the Length an d sequence of their C-termini, In rat brain, the 5-HT4S transcripts ar e restricted to the striatum, but the 5-HT4L transcripts are expressed throughout the brain, except in the cerebellum where it was barely de tectable, In peripheral tissues, differential expression was also obse rved in the atrium of the heart where only the 5-HT4S isoform was dete ctable.