ducing so many outcomes is the generation of several active peptides that signal through distinct receptors. The inactive angiotensinogen precursor Agt is the sole substrate of renin aspartyl protease whose inactive proenzyme form is prorenin. Prorenin can bind the renin receptor and display catalytic activity, presumably the consequence of an induced conformational change prompting a transition from the close-inactive to the open-active state. Receptor-bound renin has a higher catalytic activity than renin in solution. The receptor triggers several intracellular signaling pathways in a renin-dependent as well as independent fashion, the latter being promoted by a processed, truncated receptor (several MAPKs pathways are renin-dependent whereas Wnt pathways are renin-independent). A second non-specific receptor known as the mannose-6-phosphate receptor acts mostly as a clearance receptor. Binding of Renbp to renin inhibits its catalytic activity. The product of renin is the inactive peptide AgtI, in turn the substrate of Ace. Cleavage of AgtI by Ace results in the potent AgtII peptide. AgtII elicits two distinct signaling pathways via receptors type 1 and 2, Agtr1 and Agtr2, respectively. Agtr1 mediated pathway is involved in vasoconstriction, proliferation and fluid homeostasis. Its powerful but potentially harmful effects are counterbalanced by the Agtr2 mediated signaling which promotes vasodilation, NO release and growth inhibition. AgtIII, resulting from the cleavage of AgtII by the aminopeptidase Enpep, engages the same two receptors with overall similar effects. Anpep, known as aminopeptidase N or M generates AgtIV from AgtIII. The leucyl/cystinyl aminopeptidase Lnpep, also known as Irap, has been shown to be the receptor for AngIV; AngIV triggered signaling is believed to play important roles in learning and memory. Finally, the Agt1-7 peptide can be generated from AgtII through the action of Ace2 or from AgtI through the action of the neutral endopeptidease Mme. Initially Agt1-7 was thought to be inactive but subsequent studies have shown that it signals through its own receptor Mas1 to mediate vasodilation and anti-proliferation and to exert endothelial functions. Malfunctioning of the RAS system has been associated with several conditions including cardiovascular and renal. To see the ontology report for annotations, GViewer and download, click here
[click to see associated KEGG map - map04614]...(less)