id: PW:0000527 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000527 title: angiotensin ii signaling pathway via at1 receptor description: Agiotensin II (AgtII) is probably the most potent of the biologically active peptides generated by the renin-angiotensin system pathway. Overall AgtII elicits distinct responses through signaling via receptor type 1 and 2, 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 the Galphaq of heterotrimeric G proteins (in rodents and possibly other species the Galphai or Galpha12/Galpha13 may also be involved, not shown). Activated receptors act as GEFs to catalyze the release of GDP from the G alpha subunit followed by formation of a stable receptor-G protein complex. GTP binding to the alpha subunit triggers conformational re-arrangements leading to dissociation of the GTP-bound G alpha from both the receptor and the beta/gamma complexes and association with downstream effectors. Galphaq members activate phospholipase C (PLC) which hydrolyzes PIP2 to DAG and IP3; IP3 promotes calcium release from ER. DAG and calcium activate members of PKC as well as other proteins with possible roles in the Agtr1 mediated signaling. Calcium and PKC may mediate transactivation of EGF signaling which activates the Erk1/2 MAPK cascade; the cascade can be directly activated by PKC. Increase in intracellular calcium concentration could activate calcium/calmodulin dependent kinase I and IV which then activate several transcription factors that may prompt the expression of aldosterone synthase thus resulting in the biosynthesis of this steroid hormone and its subsequent signaling. RGS proteins acting as GAPs boost the intrinsic but slow GTPase activity of G alpha proteins to terminate the G-protein signal. Atgr1, phosphorylated by PKC or by specific GPCR kinases (GRKs), binds beta-arrestin proteins (Arbb). Binding precludes G protein coupling and leads to internalization of the receptor via Arbb1 or to further signaling via Arbb2 acting as a scaffold. Signaling via Arbb2 may occur in the absence of G protein coupling. Agtr1 can interact with Jak2 thus prompting the Jak-Stat signaling. Like in the case of Arbb2, the Agrt1 induced activation of Jak-Stat may occur in the absence of G protein coupling. The receptor binds a variety of other proteins; for some interactors, the role they play in AgtII signaling via Agtr1 remains to be documented. Others have been shown to promote receptor internalization like in the case of Agtrap or receptor recycling in the case Arap-1, leading to termination or stimulation of the signal, respectively. Agtr1 mediated signaling stimulates the synthesis of aldosterone in both the acute and the chronic responses. The expression of several transcription factors that control enzymes involved in aldosterone biosynthesis, is increased upon stimulation with AgtII. In addition, calcium stimulates calmodulin dependent protein kinase leading to phosphorylation of transcription factors with a role in aldosterone synthesis and release. In addition to potential G protein independent signaling, Agtr1 may be activated in the absence of ligand binding. The powerful but potentially harmful effects elicited by Agtr1 are counterbalanced by the Agtr2 mediated signaling. Deregulation of Agtr1 mediated signaling has been involved in several conditions. diagram_image: https://rgd.mcw.edu/pathway/PW0000527/angiotensin%20II%20signaling%20pathway%20via%20AT1%20receptor/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000527/angiotensin%20II%20signaling%20pathway%20via%20AT1%20receptor/angiotensin%20II%20signaling%20pathway%20via%20AT1%20receptor.gpp diagram_pathway_links: - id: PW:0000102 label: the extracellular signal-regulated Raf/Mek/Erk signaling pathway - id: PW:0000170 label: epidermal growth factor/neuregulin signaling pathway - id: PW:0000209 label: Jak-Stat signaling pathway - id: PW:0000229 label: G protein mediated signaling pathway via Galphaq family - id: PW:0000492 label: renin-angiotensin system signaling pathway - id: PW:0000840 label: protein kinase C (PKC) signaling pathway - id: PW:0001139 label: calcium transport pathway - id: PW:0001140 label: calcium/calcium-mediated signaling pathway diagram_gene_links: - id: RGD:2069 label: Agt - id: RGD:2070 label: Agtr1 - id: RGD:2071 label: Agtr1b - id: RGD:1359346 label: Agtrap - id: RGD:1310385 label: Arap1 - id: RGD:2156 label: Arrb1 - id: RGD:2157 label: Arrb2 - id: RGD:619749 label: Gna11 - id: RGD:620770 label: Gnaq - id: RGD:2939 label: Jak2 - id: RGD:621665 label: Rgs2 diagram_chemicals: - id: HMDB:HMDB01035 label: AgtII - id: CHEBI:29108 label: Ca2+ - id: CHEBI:18035 label: DAG - id: CHEBI:16595 label: IP3 diagram_edges: - source: Agt relation: positively_affects target: AgtII - source: AgtII relation: associated_with target: Agtr1 - source: AgtII relation: associated_with target: Agtr1b - source: AgtII relation: positively_affects target: cell proliferation - source: AgtII relation: positively_affects target: hormone release - source: AgtII relation: positively_affects target: kidney function - source: AgtII relation: positively_affects target: vasoconstriction - source: Agtr1 relation: associated_with target: Agtrap - source: Agtr1 relation: associated_with target: Arap1 - source: Agtr1 relation: associated_with target: Arrb1 - source: Agtr1 relation: associated_with target: Arrb2 - source: Agtr1 relation: associated_with target: Gna11 - source: Agtr1 relation: associated_with target: Gnaq - source: Agtr1 relation: associated_with target: Jak2 - source: Agtr1b relation: associated_with target: Gna11 - source: Agtr1b relation: associated_with target: Gnaq - source: Agtrap relation: negatively_affects target: Agtr1 - source: GRK members relation: positively_affects target: Agtr1 - source: Rgs2 relation: negatively_affects target: Gna11 - source: Rgs2 relation: negatively_affects target: Gnaq - source: protein kinase C (PKC) signaling pathway relation: positively_affects target: epidermal growth factor/neuregulin signaling pathway diagram_labels: - Arap1 --+> Agtr1 - Ca2+ --+> protein kinase C (PKC) signaling pathway - cell proliferation - DAG --+> protein kinase C (PKC) signaling pathway - EGF transactivation - Gnaq --+> DAG - Gnaq --+> IP3 - hormone release - IP3 --+> Ca2+ - kidney function - protein kinase C (PKC) signaling pathway --+> the extracellular signal-regulated Raf/Mek/Erk signaling pathway - receptor internalization - receptor recycling - vasoconstriction diagram_other_links: - href: /wg/home/pathway2/molecular-pathways2/grk-members label: GRK members 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. Epub 2005 Sep 1. - id: RGD:5133417 citation: Shenoy SK and Lefkowitz RJ, Sci STKE. 2005 Nov 22;2005(311):cm14. - id: RGD:5133662 citation: Higuchi S, etal., Clin Sci (Lond). 2007 Apr;112(8):417-28. - id: RGD:5133663 citation: Aplin M, etal., Trends Cardiovasc Med. 2008 Nov;18(8):305-12. - id: RGD:5133665 citation: Aplin M, etal., J Mol Cell Cardiol. 2009 Jan;46(1):15-24. Epub 2008 Sep 26. - id: RGD:5133666 citation: Oliveira L, etal., Physiol Rev. 2007 Apr;87(2):565-92. - id: RGD:5133667 citation: Thomas WG and Qian H, Trends Endocrinol Metab. 2003 Apr;14(3):130-6. - id: RGD:5133668 citation: Mogi M, etal., Curr Opin Nephrol Hypertens. 2009 Mar;18(2):138-43. - id: RGD:5133669 citation: Mogi M, etal., Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2532-9. Epub 2007 Aug 23. - id: RGD:5133670 citation: Spat A and Hunyady L, Physiol Rev. 2004 Apr;84(2):489-539. - id: RGD:5133671 citation: Nogueira EF, etal., Mol Cell Endocrinol. 2009 Apr 29;302(2):230-6. Epub 2008 Sep 3. - id: RGD:5133672 citation: Willenberg HS, etal., Horm Metab Res. 2008 Jul;40(7):435-41. Epub 2008 May 20. - id: RGD:5135301 citation: Lemarie CA, etal., J Mol Med (Berl). 2008 Jun;86(6):673-8. Epub 2008 Mar 27.