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Loss-of-Function Polymorphic Variants of the Human Angiotensin II Type 1 Receptor

Laboratory of Molecular Cardiology, the Heart Centre and Copenhagen Heart Arrhythmia Research Centre, Copenhagen University Hospital Section 9312, and the Faculty of Health, University of Copenhagen, Denmark (J.L.H., S.H., S.P.S.); ACADIA Pharmaceuticals Inc., San Diego, California (J.L.H., M.R.B, D.M.W.); and Departments of Pharmacology (M.R.B.), Neurosciences (D.M.W.), and Psychiatry (D.M.W.), University of California at San Diego, La Jolla, California.

The angiotensin II type 1 (AT₁) receptor is the primary effector for angiotensin II (Ang II), a key peptide regulator of blood pressure and fluid homeostasis. AT₁ receptors are involved in the pathogenesis of several cardiovascular diseases, including hypertension, cardiac hypertrophy, and congestive heart failure, which are characterized by significant interindividual variation in disease risk, progression, and response to pharmacotherapy. Such variation could arise from genomic polymorphisms in the AT₁ receptor. To pursue this notion, we have pharmacologically characterized seven known and putative nonsynonymous AT₁ receptor variants. Functional analysis using the cell-based assay receptor selection and amplification technology (R-SAT) revealed that three variants (AT₁-G45R, AT₁-F204S, and AT₁-C289W) displayed altered responses to Ang II and other AT₁ receptor agonists and antagonists. Agonist responses to Ang II were absent for AT₁-G45R and significantly reduced in potency for AT₁-C289W (11-fold) and AT₁-F204S (57-fold) compared with the wild-type (WT) receptor. AT₁-F204S also displayed reduced relative efficacy (57%). Quantitatively similar results were obtained in two additional functional assays, phosphatidyl inositol hydrolysis and extracellular signal-regulated kinase activation. Radioligand binding studies revealed that AT₁-G45R failed to bind Ang II, whereas cell surface staining clearly showed that it trafficked to the cell surface. AT₁-C289W and AT₁-F204S displayed reduced binding affinities of 3- and 5-fold and reduced cell surface expression of 43 and 60% of that observed for the WT receptor, respectively. These data demonstrate that polymorphic variation in the human AT₁ receptor induces loss of functional phenotypes, which may constitute the molecular basis of variability of AT₁ receptor-mediated physiological responses.

Received August 8, 2003; accepted November 17, 2003.

Address correspondence to: Dr. Jakob Lerche Hansen, Laboratory of Molecular Cardiology, The Heart Centre and Copenhagen Heart Arrhythmia Research Centre, Copenhagen University Hospital Section 9312, and the Faculty of Health, University of Copenhagen, 20 Juliane Mariesvej, DK-2100, Copenhagen, Denmark. E-mail: jlhansen{at}molheart.dk

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