The amino terminus of the AT2 receptor is critical for AngII binding but not for AT2-selective ligands, and can be functionally compensated by the AT1 amino terminus despite sequence differences.
Preclinical findings preclude practice change; leaves open AT2-selective ligand design targeting non-amino-terminal domains.
Key amino terminal residues in type 1 (AT1) angiotensin II (AngII) receptors are not conserved within type 2 (AT2) receptors. We therefore characterized amino terminal mutants that are transiently expressed in COS-3 membranes. AT2 amino terminal deletion drastically reduced affinity for AngII, suggesting its importance for this subtype. AT1-AT2 amino terminal exchanges retained wild type AngII affinities (Kd ranging from 3-5 nM), indicating compensation despite substantial sequence dissimilarities. Finally, binding of AT2 selective ligands (CGP42112A and PD123319) was not dependent on the amino terminus.
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Yee et al. (1998) studied this question.
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