Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: MOLECULAR MECHANISMS OF ANGIOTENSIN II (AT1a) RECEPTOR ENDOCYTOSIS

• 1 Angiotensin II (AngII) initiates a variety of cellular responses through activation of type 1 (AT₁; with subtypes AT_1a and AT_1b) and type 2 (AT₂) cell surface angiotensin receptors. Both AT₁ and AT₂ receptors couple to heterotrimeric guanyl nucleotide binding proteins (G-proteins) and generate intracellular signals following recognition of extracellular AngII, but only AT₁ is targeted for the rapid ligand-stimulated endocytosis (internalization) typical of many plasma membrane receptors.
• 2 AT₁ endocytosis proceeds through clathrin-coated pits and is independent of G-protein coupling which predicts that the AngII-AT₁ receptor complex attains a conformation necessary for interaction with the endocytotic machinery, but separate from receptor signalling activation.
• 3 The function of AT₁ endocytosis and the reason for the disparity between AT₁ and AT₂ endocytosis is not fully appreciated, but the latter probably reflects differences in the primary amino acid sequence of these two receptor types.
• 4 For many receptors that undergo internalization, it has been established that internalization motifs (2–6 amino acids, often incorporating crucial tyrosine and hydrophobic amino acids) within the cytoplasmic regions of the receptor mediate the selective recruitment of activated receptors into clathrin-coated pits and vesicles.
• 5 Mutagenesis studies on the AT_1a receptor, aimed at identifying such motifs, reveal that sites within the third cytoplasmic loop and the cytoplasmic carboxyl terminal region are important for AngII-stimulated AT_1a receptor endocytosis.