oconstriction, 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. To see the ontology report for GViewer, annotations and download, click here

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