id: PW:0000244 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000244 title: angiotensin ii signaling pathway description: Agiotensin II (AgtII), the product of Ace action in the renin-angiotensin system, is probably the most potent of the biologically active peptides the pathway generates. The system, originally viewed as solely endocrine, is now regarded as an endocrine, paracrine and autocrine one, producing an array of diverse and many times opposing actions via both the 'classical' or circulatory and the local or 'tissue' routes. Overall AgtII elicits distinct responses through signaling via receptor type 1 and2, Agtr1 and Agtr2, respectively. Of the two receptors, Agtr1 which is expressed in most tissues and which in rodents is represented by two genes that are 95% identical in their amino acid sequences, is the better understood system. The Agtr1 mediated pathway is involved in vasoconstriction, proliferation, hormone release and fluid homeostasis. Activated Agtr1 couples to members of the Galphaq family of heterotrimeric G proteins whose signal transduction leads to activation of phopholipase C followed by activation of protein kinase C signaling pathway and the events downstream of it. In response to AgtII, Agtr1 can also mediate G protein independent signaling. In addition, Agtr1 may be active in the absence of ligand binding. The powerful but potentially harmful effects elicited by Agtr1 are counterbalanced by the Agtr2 mediated signaling. This pathway promotes vasodilation, NO release and growth inhibition. Agtr2, initially believed not to engage heterotrimeric G proteins was later shown to couple to members of the Galphai family. Agtr2 activates several protein phosphatases in a G protein dependent and independent manner resulting in inactivation of MAPK cascades thus conducive to antiproliferative effects. Agtr2 also prompts release of nitric oxide (NO) and increase in intracellular cGMP levels in a manner that is both dependent and independent of bradykinin receptor 2 (B2) and leading to vasodilator effects. Like in the case of Agtr1, Agtr2 mediated signaling can be G protein as well as ligand independent. However, the molecular mechanisms of Agtr2 mediated signaling are not well understood and the currently available information, at times is thought of as being controversial. Agtr1 and Agtr2 can form homodimers as well as heterodimers with other GPCRs and with one another. Deregulation of AgtII signaling has been implicated in cardiovascular and renal disorders. diagram_image: https://rgd.mcw.edu/pathway/PW0000244/angiotensin%20II%20signaling%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000244/angiotensin%20II%20signaling%20pathway/angiotensin%20II%20signaling%20pathway.gpp diagram_pathway_links: - id: PW:0000228 label: G protein mediated signaling pathway via Galphai family - id: PW:0000229 label: G protein mediated signaling pathway via Galphaq family - id: PW:0000492 label: renin-angiotensin system signaling pathway - id: PW:0000527 label: angiotensin II signaling pathway via AT1 receptor - id: PW:0000528 label: angiotensin II signaling pathway via AT2 receptor - id: PW:0000840 label: protein kinase C (PKC) signaling pathway diagram_gene_links: - id: RGD:2069 label: Agt - id: RGD:2070 label: Agtr1a - id: RGD:2071 label: Agtr1b - id: RGD:2072 label: Agtr2 diagram_chemicals: - id: HMDB:HMDB01035 label: AgtII diagram_edges: - source: Agt relation: positively_affects target: AgtII - source: AgtII relation: associated_with target: Agtr1a - source: AgtII relation: associated_with target: Agtr1b - source: AgtII relation: associated_with target: Agtr2 - source: AgtII relation: positively_affects target: antiproliferation - source: AgtII relation: positively_affects target: fluid homeostasis - source: AgtII relation: positively_affects target: hormone release - source: AgtII relation: positively_affects target: vasoconstriction - source: AgtII relation: positively_affects target: vasodilation - source: Agtr1a relation: positively_affects target: Agtr1, G protein/ligand independent signaling - source: Agtr1b relation: positively_affects target: Agtr1, G protein/ligand independent signaling - source: Agtr2 relation: positively_affects target: Agtr2, G protein/ligand independent signaling diagram_labels: - Agtr1, G protein/ligand independent signaling - Agtr2, G protein/ligand independent signaling - antiproliferation - fluid homeostasis - hormone release - vasoconstriction - vasodilation references: - id: RGD:1581825 citation: de Gasparo M, etal., Pharmacol Rev. 2000 Sep;52(3):415-72. - id: RGD:1581847 citation: Hunyady L and Catt KJ, Mol Endocrinol. 2006 May;20(5):953-70. 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