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Residues Val²⁵⁴, His²⁵⁶, and Phe²⁵⁹ of the Angiotensin II AT₁ Receptor Are Not Involved in Ligand Binding but Participate in Signal Transduction

Department of Biophysics Escola Paulista de Medicina Federal University of São Paulo 04023–062 São Paulo, SP, Brazil

The role of the external third of helix VI of the angiotensin II (AII) AT₁ receptor for the interaction with its ligand and for the subsequent signal transduction was investigated by individually replacing residues 252–256 by Ala, and residues 259 or 261 by Tyr, and permanently transfecting the resulting mutants to Chinese hamster ovary (CHO) cells. Binding experiments showed no great changes in affinity of any of the mutants for AII, [Sar¹]-AII, or [Sar¹, Leu⁸]-AII, but the affinity for the nonpeptide antagonist DuP753 was significantly decreased. The inositol phosphate response to AII was remarkably decreased in mutants V254A, H256A, and F259Y. These results indicate that AT₁ residues Val²⁵⁴, His²⁵⁶, and Phe²⁵⁹ are not involved in ligand binding but participate in signal transduction. Based in these results and in others from the literature, it is suggested that, in addition to the His²⁵⁶ imidazole ring, the Phe²⁵⁹ aromatic ring interacts with the AII’s Phe⁸, thus contributing to the signal-triggering mechanism.

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