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Single Mutations at Asn²⁹⁵ and Leu³⁰⁵ in the Cytoplasmic Half of Transmembrane -Helix Domain 7 of the AT₁ Receptor Induce Promiscuous Agonist Specificity for Angiotensin II Fragments: A Pseudo-Constitutive Activity

Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland (Y.-H.F., R.Q.); and Department of Medicine, CWRU School of Medicine, Cleveland, Ohio (L.Z., R.Z.)

The most striking feature of a G protein-coupled receptor (GPCR) is its highly exclusive agonist specificity. This feature guarantees that a GPCR recognizes only its specific native agonist(s). In this study, we showed that two point mutations of N295S and L305Q enabled the AT₁ receptors to recognize multiple Ang II fragments. Similar to the well established constitutively active AT₁ mutant receptor N111G, the mutations of N295S and L305Q induced an increased production of basal inositol 1,4,5-phosphates in the absence of exogenous Ang II when expressed in HEK293 cells. Distinct from the N111G, however, is the fact that the increased basal activity disappeared in COS-7 cells because of the lack of endogenous Ang II fragments produced by the cells—a pseudo-constitutive activity. It is surprising that the Ang II analog [Sar¹,Ile⁴,Ile⁸]Ang II and the native angiotensin II fragments Ang 1-7, Ang IV, and Ang 5-8, which are inactive in activating the wild-type receptor, activated N295S and L305Q. Results generated by lowering the Na⁺ concentration suggest that the mutant N295S and L305Q may be trapped in neutral conformational states (R^N). These data allow us to identify for the first time a novel pattern of GPCR mutations with a broad spectrum of agonist specificity, suggesting possible existence of functional GPCRs in nature that are activated through conformational "selection" rather than "induction" mechanisms.

Address correspondence to: Dr. Ying-Hong Feng, Department of Pharmacology, C2021, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814. E-mail: yhfeng{at}usuhs.mil

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