RGD Reference Report - Global analysis of the effects of the V2 receptor antagonist satavaptan on protein phosphorylation in collecting duct. - Rat Genome Database

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Global analysis of the effects of the V2 receptor antagonist satavaptan on protein phosphorylation in collecting duct.

Authors: Hoffert, Jason D  Pisitkun, Trairak  Saeed, Fahad  Wilson, Justin L  Knepper, Mark A 
Citation: Hoffert JD, etal., Am J Physiol Renal Physiol. 2014 Feb 15;306(4):410-21. doi: 10.1152/ajprenal.00497.2013. Epub 2013 Nov 20.
RGD ID: 401827158
Pubmed: PMID:24259510   (View Abstract at PubMed)
PMCID: PMC3920024   (View Article at PubMed Central)
DOI: DOI:10.1152/ajprenal.00497.2013   (Journal Full-text)

Satavaptan (SR121463) is a vasopressin V2 receptor antagonist that has been shown to improve hyponatremia in patients with cirrhosis, congestive heart failure, and syndrome of inappropriate antidiuresis. While known to inhibit adenylyl cyclase-mediated accumulation of intracellular cyclic AMP and potentially recruit β-arrestin in kidney cell lines, very little is known regarding the signaling pathways that are affected by this drug. To this end, we carried out a global quantitative phosphoproteomic analysis of native rat inner medullary collecting duct cells pretreated with satavaptan or vehicle control followed by the V2 receptor agonist desmopressin (dDAVP) for 0.5, 2, 5, or 15 min. A total of 2,449 unique phosphopeptides from 1,160 proteins were identified. Phosphopeptides significantly changed by satavaptan included many of the same kinases [protein kinase A, phosphoinositide 3-kinase, mitogen-activated protein kinase kinase kinase 7 (TAK1), and calcium/calmodulin-dependent kinase kinase 2] and channels (aquaporin-2 and urea transporter UT-A1) regulated by vasopressin. Time course clustering and kinase motif analysis suggest that satavaptan blocks dDAVP-mediated activation of basophilic kinases, while also blocking dDAVP-mediated inhibition of proline-directed kinases. Satavaptan affects a variety of dDAVP-mediated processes including regulation of cell-cell junctions, actin cytoskeleton dynamics, and signaling through Rho GTPases. These results demonstrate that, overall, satavaptan acts as a selective V2 receptor antagonist and affects many of the same signaling pathways regulated by vasopressin. This study represents the first "systems-wide" analysis of a "vaptan"-class drug and provides a wealth of new data regarding the effects of satavaptan on vasopressin-mediated phosphorylation events.



Gene-Chemical Interaction Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MAP3K7Humansatavaptan decreases phosphorylationISOMap3k7 (Rattus norvegicus)Satavaptan decreases phosphorylation of Map3k7 protein in inner medullary collecting ductRGD 
Map3k7Ratsatavaptan decreases phosphorylationEXP Satavaptan decreases phosphorylation of Map3k7 protein in inner medullary collecting ductRGD 
Map3k7Mousesatavaptan decreases phosphorylationISOMap3k7 (Rattus norvegicus)Satavaptan decreases phosphorylation of Map3k7 protein in inner medullary collecting ductRGD 

Objects Annotated

Genes (Rattus norvegicus)
Map3k7  (mitogen activated protein kinase kinase kinase 7)

Genes (Mus musculus)
Map3k7  (mitogen-activated protein kinase kinase kinase 7)

Genes (Homo sapiens)
MAP3K7  (mitogen-activated protein kinase kinase kinase 7)


Additional Information