id: PW:0000713 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000713 title: vasopressin signaling pathway via receptor type 2 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. 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; theregulation 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. The compartmentalization of PKA signal is regulated by the AKAP family of scaffold proteins ( A K inase A nchoring P rotein). AKAPs bring together PKA, the phosphatases and phosphodiesterases (PDE) that modulate the cAMP signal and in certain cases, substrates and AC. Akap7 and members of PDE4 family are associated with Aqp2 bearing vesicles. PKA phosphorylation at serine 256 of human AQP2 is essential for the translocation of the channel. Phosphorylation of transcription factor Creb at serine 133 is necessary for its activation and the subsequent transcription of its many target genes, one of which is Aqp2. PKA also phosphorylates Pde4d, thus regulating its own activity. Cytoskeletal and membrane fusion/docking components involved in the trafficking of Aq2p-bearing vesicles include at a minimum myosin Vb - recruited to vesicles via its receptor Rab11 and the Rab11fip2 mediator, the v-SNARE Vamp2, the t-SNARE Snap23 and syntaxin (3 or 4). In addition, the PDZ domain containing Sipa1 has been identified as a binding partner for Aqp2; its GAP activity towards Rap1 is necessary for the translocation of the channel (Rap1 is involved in actin polymerization). Calcium appears to mediate a cAMP dependent but PKA independent mechanism of Aqp2 translocation. cAMP promotes the transcription of Aqp2; the role of PKA and thus of vasopressin might be by-passed. Withdrawal of Avp signal or hydrolysis of cAMP leads to internalization of Aqp2. Several disorders and syndromes are associated with disturbances in the Aqp2-mediated water transport, in particular congenital Nephrogenic Diabetes Insipidus (NDI), caused by mutations in Avpr2 and more rarely, in Aqp2. diagram_image: https://rgd.mcw.edu/pathway/PW0000713/vasopressin%20signaling%20pathway%20via%20receptor%20type%202/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000713/vasopressin%20signaling%20pathway%20via%20receptor%20type%202/vasopressin%20signaling%20pathway%20via%20receptor%20type%202.gpp diagram_pathway_links: - id: PW:0000227 label: G protein mediated signaling pathway via Galphas family - id: PW:0000543 label: protein kinase A (PKA) signaling pathway diagram_gene_links: - id: RGD:2035 label: Adcy6 - id: RGD:1303071 label: Akap7 - id: RGD:2142 label: Aqp2 - id: RGD:2184 label: Avp - id: RGD:2186 label: Avpr2 - id: RGD:2716 label: Gnas - id: RGD:621347 label: Myo5b - id: RGD:3281 label: Pde4d - id: RGD:619762 label: Rab11a - id: RGD:1308538 label: Rab11fip2 - id: RGD:1303184 label: Sipa1 - id: RGD:620221 label: Snap23 - id: RGD:3949 label: Vamp2 diagram_chemicals: - id: PUBCHEM.COMPOUND:5957 label: ATP - id: PUBCHEM.COMPOUND:6076 label: cAMP - id: PUBCHEM.COMPOUND:962 label: water diagram_edges: - source: ATP relation: positively_affects target: cAMP - source: Akap7 relation: associated_with target: Pde4d - source: Akap7 relation: associated_with target: protein kinase A (PKA) signaling pathway - source: Aqp2 relation: associated_with target: Sipa1 - source: Avp relation: associated_with target: Avpr2 - source: Avpr2 relation: associated_with target: Gnas - source: Myo5b relation: associated_with target: Rab11a - source: Myo5b relation: associated_with target: Rab11fip2 - source: Pde4d relation: negatively_affects target: cAMP - source: Rab11a relation: associated_with target: Rab11fip2 - source: water relation: positively_affects target: water reabsorption diagram_labels: - cAMP --+> protein kinase A (PKA) signaling pathway - Gnas --+> Adcy6 - protein kinase A (PKA) signaling pathway --+> Aqp2 - protein kinase A (PKA) signaling pathway --+> Pde4d - 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. 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