Published Online
on July 5, 2005

A more recent version of this article appeared on August 1, 2005

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Submitted on March 7, 2005
Revised on March 27, 2005

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; and 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.

^* To whom correspondence should be addressed. E-mail: yhfeng{at}usuhs.mil.

Abstract--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 -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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