Fig. 3.

Model of pathways through which the iRAS may mediate intracellular effects. [1] Endosomes containing embedded AT₁R can be internalized and AT₁R can continue to signal through the β-arrestin:AT₁R complex which serves as a scaffold for assembly of ERK and JNK signaling components (142). [2] Acidification of endosomes (20, 24) permits release of ANG II into the cytoplasm, where it may traffic to nucleus [3] or mitochondria [4], either free or bound to other proteins. Cytosolic ANG II can mediate signaling effects by modifying protein complex activity, or it can be transported into the nucleus as a complex or as a free peptide. In the nucleus, association of ANG II with other proteins, including, potentially, a nuclear form of ANG II receptor may permit modification of gene expression or DNA replication. In addition, a cleaved fragment of the AT₁R (COOH terminus) (28) [5, 6] may associate with a protein complex that includes ANG II [7] and traffic to nucleus [8]. AT₁R can accumulate in nuclear membrane (11, 30) presumably by retrograde membrane diffusion from the endoplasmic reticulum (ER)/Golgi apparatus. Receptor associated with the inner nuclear membrane [by movement from the outer nuclear membrane around the nuclear pore complex (137, 166)] is positioned such that the COOH terminus is within the nucleosol [9] and available for signaling through nuclear second messenger signaling pathways (11, 12, 16, 81, 125). Presumably, nuclear signaling through nuclear membrane-associated AT₁R is ligand mediated. We believe that ANG II may gain access to the ER lumen and, subsequently, to the intranuclear membrane space, via trafficking through the slow recycling endosome pathway (30, 67). [10] In addition, ANG II may be generated within cells from intracellular AGT (30, 143).