Genomic DNA analysis revealed that the coding region of the rat histamine H-3 receptor comprises three exons interrupted by two introns of similar to1 kb each. Several H-3 receptor mRNA variants were identified by PCR and cDNA cloning and sequencing. Four variants generated by pseudo-intron retention/deletion at the level of the third intracellular loop were designated H-3(445), H-3(413), H-3(410), and H-3(397), according to the length of their deduced amino acid sequence and display differential tissue expression. When expressed in CHO-K1 or Cos-1 cells, the H-3(445), H-3(413), and H-3(397) were found to generate specific [I-125]iodoproxyfan binding of similar pharmacological profile. In addition, we identified two short variants, termed H-3(nf1) and H-3(nf2), which correspond to frame shift and stop codon interposition, respectively, and are presumably nonfunctional, among which H-3(nf2), displays brain expression similar to that of the longer isoforms.