Several interesting phenotypes of the AT(1) receptor produced by site-directed mutagenesis

The angiotensin II (AngII) AT(1) receptor is a seven-transmembrane domain r eceptor coupled to a Gq/11 protein and phospholipase C, but also to other G proteins and to several tyrosine kinase pathways. These signaling pathways transduce inside the cells the classical actions of AngII (vasoconstrictio n, aldosterone secretion, etc.), but also the mitogenic action of this vaso active peptide. In the past 5 yr, site-directed mutagenesis has elucidated the molecular determinants of the AngII and nonpeptidic analogue-binding si tes together with those of G protein interaction. In addition, these studie s have demonstrated that modifications of the specific interactions between transmembrane domains are responsible for the activation of the receptor. Therefore, several mutations of these domains are able to block the recepto r in active or inactive states. Finally, these mutagenesis studies identify two interesting phenotypes of the AT(1) receptor. (l) A carboxy-terminal t runcation of the AT(1) receptor produces a mutant that is unable to be inte rnalized and desensitized and therefore is functionally hyper-reactive. (2) A replacement of the distal part of the third intracellular loop of the AT (1) receptor by the homologous segment of the beta(2)-adrenergic receptor p roduces a mutant coupled to both Gq and Gs proteins, which is unable to tra nsduce the mitogenic action of AngII.