Divergent conformational requirements for angiotensin II receptor internalization and signaling

Abstract

Internalization is a general feature of plasma membrane receptors, including those for nutrients (such as LDL, transferrin), growth factors (insulin, EGF, FGF, etc.), and agonists that activate U protein-coupled responses (-adrenergic and muscarinic ligands, peptide hormones, etc.). The function of this process in delivering nutrients to the cells is well established, for example, via the LDL and the transferrin receptors. The internalization process also plays a key role in regulating the number of cellsurface receptors for hormones and growth factors, and has been proposed to be important for resensitization of /3-adrenergic and possibly other receptors [11. In addition, recent data indicate that the receptor internalization process might have a function in the signal generation process of growth factor and Ca2 mobilizing receptors [2—4]. Internalization of plasma-membrane receptors is preceded by accumulation of the receptors in specialized coated pit regions of the cell surface. Coated pits invaginate and pinch off to form coated vesicles that carry the receptor into the cell. The contents of the endocytic vesicles accumulate in endosomes, and the internalized receptors and their ligands either recycle to the cell surface or are targeted for lysosomal degradation. The processes responsible for internalization of cell-surface receptors can be divided into two major groups. Most nutrient receptors undergo constitutive internalization, whereas hormone and growth factor receptors that generate intracellular signals, undergo endocytosis that is activated by their specific ligands [1, 2, 5, 6]. The assembly unit of the polygonal lattice on the surface of coated pits and vesicles is the clathrin triskeleton. Clathrin tnskeletons are three-legged structures consisting of three heavy chains and three tightly associated light chains [7]. Most available data indicate that the clathnin structure binds to the membrane via one of the major classes of coat proteins recently named adaptor proteins (APs) [7]. Two structurally related classes of APs are present in most cell types. Immunofluorescence studies revealed that the APi complex colocalizes with the Golgi-associated coated pits, while the AP2 is found in plasma membrane-associated