Human type-1 angiotensin II (AT1) receptor gene structure and function

1. The type-1 angiotensin II (AngII) receptors, designated AT(1), mediate most of the biological actions of the peptide hormone AngII. They are the most recent drug target for the treatment of hypertension and cardiac failure and basic research is now focusing on the mechanisms that regulate their expression. 2. In humans there is a single AT(1) gene. It encodes a 47 kb pre-mRNA containing five exons, with the previously described AT(1) open reading frame (ORF) on exon 5. Alternative splicing results in the production of mature mRNA that are translated at different efficiencies and encode two receptor isoforms. The inclusion of exon 2 markedly inhibits translation of the downstream ORF, both in vitro and in vivo. Nonetheless, this exon is present in up to one-half of AT(1) mRNA in all tissues studied. 3. Transcripts containing exon 3 spliced to exon 5 encode a receptor with an amino-terminal extension of 32 amino acids and represent up to one-third of total AT(1) mRNA in each tissue examined. In vitro, these latter transcripts are translated to produce a longer receptor and, in transfected cells, they encode a functional AT(1) receptor with ligand-binding and signalling properties similar to those of the short isoform. 4. Exon 4 is of minor significance as it is rarely spliced into AT(1) mRNA. 5. These data indicate that, in addition to characterizing factors that modulate AT(1) promoter activity and RNA stability, it is important to analyse the splicing patterns of this gene when studying the regulation of its expression.