Angiotensin II type 1 receptor‐function affected by mutations in cytoplasmic loop CD

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Abstract
To explore peptide hormone‐induced conformational changes, we attempted to engineer a metal–ion binding site between the cytoplasmic loops CD and EF in the angiotensin II type 1 (AT1) receptor. We constructed 12 double and six triple histidine mutant receptors, and tested the ability of each mutant and the wild‐type to activate inositol phosphate (IP) production with and without ZnCl2. Inhibition by ZnCl2 in the double and triple His mutant receptors was not significant, but these mutations directly decreased the IP production. Systematic analysis of single His mutants demonstrated that the loop CD‐mutants displayed 52–74% inhibition of IP production, whereas the loop EF‐mutants did not affect IP production. These results indicate that the cytoplasmic loop CD‐segment from Tyr127 to Ile130 is important for Gq/11 activation by the AT1 receptor.