MECHANISM OF ANGIOTENSIN II (AT1A) RECEPTOR ENDOCYTOSIS

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Endocytosis of cell surface receptors dampens cell responses and mediates cellular resensitization. Endocytosing receptors contain internalization motifs in their cytoplasmic domains which interact with the endocytic machinery and facilitate receptor migration and internalization upon ligand stimulation. The angiotensin-II (AT1A) G- Protein coupled receptor contains two cytoplasmic tail regions which contribute to ligand-stimulated endocytosis. The overall goal of this proposal is to test the hypothesis that amino acid residues previously identified as important for internalization of AT1A contribute to internalization motifs which interact with endocytic machinery to facilitate internalization. In AIM 1, we will fully characterize these motifs by specifically mutating amino acids surrounding the previously identified important residues. In AIM Il, we will construct chimeric receptors containing regions of the non- internalizing AT2 and segments of AT1A deemed to be important for internalization in order to determine the role of these regions in AT1A endocytosis. Finally, in AIM III, we will determine specific regions or amino acids of the AT1A carboxyl tail which interact with the endocytotic machinery.