id: PW:0000491 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000491 title: vasopressin signaling pathway description: Vasopressin (Avp) acts as an antidiuretic hormone and as a neuromodulator and neurotransmitter. Avp exerts its actions by binding to two receptor types, G-protein coupled receptors coupling to particular G alpha subunits of heterotrimeric G proteins. Avp plays important roles in the cardiovascular and autonomic function by signaling via receptor type 1a (Avpr1a). The receptor couples to Gq alpha subunit leading to stimulation of phospholipase C beta isoforms, subsequent generation of second messengers and increase in intracellular calcium resulting in vasoconstriction. The receptor is expressed in vascular smooth muscle and also in the liver, platelets and the brain. The susceptibility of the receptor to cellular proteases has made its study rather difficult. The human type 1b (AVPR1B), also known as vasopressin receptor 3 receptor is expressed in the pituitary and due to its scarcity is the least characterized system (not shown). Vasopressin signaling via receptor type 1 is also believed to mediate behavioral effects. An important and probably the best characterized role of Avp is in the regulation of water homeostasis by signaling via receptor type 2. Water homeostasis is maintained through the regulation of intravascular blood volume and osmolality; the regulation of water excretion by the kidney represents an essential aspect. Most of the water filtered by the glomeruli is constitutively reabsorbed; a percentage of it is reabsorbed in the renal collecting duct. Avp signaling via receptor type 2 (Avpr2) mediates the process by regulating the translocation of aquaporin channel 2 (Aqp2) from intracellular vesicles to the apical plasma membrane. Avpr2 couples to Gs alpha subunit leading to activation of adenylyl cyclase (ACs), subsequent production of cyclic AMP and triggering of protein kinase A pathway. PKA signaling, a widely used intracellular pathway, is the major route for channeling the cAMP signal. PKA regulates both the translocation and the expression of Aqp2. PKA phosphorylation at serine 256 of human AQP2 is essential for translocation of the channel; PKA phosphorylation of transcription factor Creb at serine 133 leads to its activation and subsequent transcription of Aqp2, one of Creb’s many targets. PKA also regulates its own activity by phosphorylating and activating the phosphodiesterases that hydrolyze and terminate the cAMP signal. Calcium appears to mediate a cAMP dependent but PKA independent mechanism of Aqp2 translocation. As cAMP activates Creb, transcription of Aqp2 could be promoted by routes that do not involve PKA signaling. Alterations in vasopressin signaling pathway have been associated with septic shock and nephrogenic diabetes insipidus. The diagram presents an overall picture of vasopressin roles and signaling via receptor type 1 and receptor type 2 and associated intracellular pathways. For more details, check the diagrams for vasopressin signaling pathway via receptor type 2 and the protein kinase A (PKA) signaling pathway – a main route mediating Aqp2 translocation and expression. diagram_image: https://rgd.mcw.edu/pathway/PW0000491/vasopressin%20signaling%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000491/vasopressin%20signaling%20pathway/vasopressin%20signaling%20pathway.gpp diagram_pathway_links: - id: PW:0000227 label: G protein mediated signaling pathway via Galphas family - id: PW:0000229 label: G protein mediated signaling pathway via Galphaq family - id: PW:0000543 label: protein kinase A (PKA) signaling pathway - id: PW:0000712 label: vasopressin signaling pathway via receptor type 1 - id: PW:0000713 label: vasopressin signaling pathway via receptor type 2 diagram_gene_links: - id: RGD:2184 label: Avp - id: RGD:2185 label: Avpr1a - id: RGD:2186 label: Avpr2 diagram_chemicals: [] diagram_edges: - source: Aqp2 expression relation: positively_affects target: water reabsorption - source: Aqp2 translocation relation: positively_affects target: water reabsorption - source: Avp relation: associated_with target: Avpr1a - source: Avp relation: associated_with target: Avpr2 diagram_labels: - '[Ca] elevation' - Aqp2 expression - Aqp2 translocation - autonomic functions - Avpr1a --+> vasoconstriction - Avpr2 --+> protein kinase A (PKA) signaling pathway - behavioral effects - protein kinase A (PKA) signaling pathway --+> Aqp2 expression - protein kinase A (PKA) signaling pathway --+> Aqp2 translocation - second messengers generation - vasoconstriction - water reabsorption references: - id: RGD:734626 citation: Birnbaumer M, Trends Endocrinol Metab. 2000 Dec;11(10):406-10. - id: RGD:1579891 citation: Holmes CL, etal., Crit Care. 2003 Dec;7(6):427-34. Epub 2003 Jun 26. - id: RGD:2312656 citation: Boone M and Deen PM, Pflugers Arch. 2008 Sep;456(6):1005-24. Epub 2008 Apr 23. - id: RGD:5129745 citation: Mayr B and Montminy M, Nat Rev Mol Cell Biol. 2001 Aug;2(8):599-609. - id: RGD:5129830 citation: Henn V, etal., Biochem Soc Trans. 2005 Dec;33(Pt 6):1316-8. - id: RGD:5129832 citation: Noda Y and Sasaki S, Biol Cell. 2005 Dec;97(12):885-92. - id: RGD:5129899 citation: Barrett LK, etal., Crit Care Med. 2007 Jan;35(1):33-40. - id: RGD:5129939 citation: Ball SG Ann Clin Biochem. 2007 Sep;44(Pt 5):417-31. - id: RGD:5129975 citation: Frank E and Landgraf R, Eur J Pharmacol. 2008 Apr 7;583(2-3):226-42. Epub 2008 Jan 19. - id: RGD:5129976 citation: Raggenbass M Eur J Pharmacol. 2008 Apr 7;583(2-3):243-54. Epub 2008 Jan 30. - id: RGD:5130038 citation: Nedvetsky PI, etal., Handb Exp Pharmacol. 2009;(190):133-57.