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(Hypertension. 2005;46:419.)
© 2005 American Heart Association, Inc.

Original Articles

Unconventional Homologous Internalization of the Angiotensin II Type-1 Receptor Induced by G-Protein–Independent Signals

Ying-Hong Feng; Yaxian Ding; Shuo Ren; Lingyin Zhou; Chuan Xu; Sadashiva S. Karnik

From the Department of Pharmacology (Y.H.F., S.R.), Uniformed Services University of the Health Sciences, Bethesda, Md; Department of Medicine (Y.D., L.Z., C.X.), Case Western Reserve University School of Medicine, Cleveland, Ohio; and the Department of Molecular Cardiology (S.S.K.), Lerner Research Institute, Cleveland Clinic Foundation, Ohio.

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

Internalization of a G-protein–coupled receptor (GPCR) is essential to the desensitization, endocytosis, and signal transduction of the receptor. It has been the general view that conventional homologous internalization of a GPCR requires activation of the G-protein(s) coupled to the receptor. However, whether and how GPCR-mediated G-protein–independent signals trigger receptor internalization remains unknown, although G-protein–independent internalization has been reported. Here we show that an angiotensin II (Ang II) type-1 (AT₁) receptor mutant incapable of activating any G-protein still undergoes normal internalization. Substitution of Asp¹²⁵ with Ala and Arg¹²⁶ with Leu at the highly conserved DRY motif of the AT₁ receptor disabled the ability of the receptor to activate G-proteins, as shown by various Ang II binding studies, GDP–GTP exchange, and inositol phosphate production assays. Surprisingly, the mutant internalized normally in the presence of Ang II and transactivated the epidermal growth factor receptor (EGFR). Similar to the wild-type receptor, overexpression of a dominant-negative K220R mutant GRK2 diminished the internalization of D125A-R126L but not the transactivation of EGFR. These data indicate that G-protein–independent specific signals may also trigger homologous internalizations of the AT₁ receptor through ß-arrestin–dependent and -independent pathways, suggesting a possible mechanism for G-protein–independent activation of G-protein–coupled receptor kinases (GRKs). This may represent a general mechanism for triggering GPCR internalization.

Key Words: receptors, angiotensin II • G-protein • angiotensin II

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