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Background: The molecular recognition theory (MRT) provides a conceptual framework that could explain the evolution of intermolecular and intramolecular interaction of peptides and proteins. As such, it predicts that binding sites of peptide hormones, and its receptor binding sites were originally encoded by and evolved from complementary strands of genomic DNA. Materials and Methods: On the basis of principles underlying the MRT, we screened a rat brain complementary DNA library using an AngII followed by an endothelin- 1 (ET-1) antisense oligonucleotide probe, expecting to isolate potential cognate receptors. Results: An identical cDNA clone was isolated independently from both the AngII and ET-1 oligonucleotide screenings. Structural analysis revealed a receptor polypeptide containing a single predicted transmembrane region with distinct ET-1 and AngII putative binding domains. Functional analysis demonstrated ET-1- and AngII-specific binding as well as ET-1- and AngII-induced coupling to a Ca2+ mobilizing transduction system. Amino acid substitutions within the predicted ET-1 binding domain obliterate ET-1 binding while preserving AngII binding, thus defining the structural determinants of ET-1 binding within the dual ET-1/AngII receptor, as well as corroborating the dual nature of the receptor. Conclusions: Elucidation of the dual ET-1/AngII receptor provides further molecular genetic evidence in support of the molecular recognition theory and identifies for the first time a molecular link between the ET-1 and AngII hormonal systems that could underlie observed similar physiological responses elicited by ET-1 and AngII in different organ systems. The prominent expression of the ET- 1/AngII receptor mRNA in brain and heart tissues suggests an important role in cardiovascular function in normal and pathophysiological states.
Ruiz-Opazo, N., Hirayama, K., Akimoto, K., & Herrera, V. L. M. (1998). Molecular characterization of a dual endothelin-1/angiotensin II receptor. Molecular Medicine, 4(2), 96–108. https://doi.org/10.1007/bf03401733