title: Adenylate cyclase 6 determines cAMP formation and aquaporin-2 phosphorylation and trafficking in inner medulla.
abstract: Arginine vasopressin (AVP) enhances water reabsorption in the renal collecting duct by vasopressin V₂ receptor (V₂R)-mediated activation of adenylyl cyclase (AC), cAMP-promoted phosphorylation of aquaporin-2 (AQP2), and increased abundance of AQP2 on the apical membrane. Multiple isoforms of adenylate cyclase exist, and the roles of individual AC isoforms in water homeostasis are not well understood. Here, we found that levels of AC6 mRNA, the most highly expressed AC isoform in the inner medulla, inversely correlate with fluid intake. Moreover, mice lacking AC6 had lower levels of inner medullary cAMP, reduced abundance of phosphorylated AQP2 (at both serine-256 and serine-269), and lower urine osmolality than wild-type mice. Water deprivation or administration of the V₂R agonist dDAVP did not increase urine osmolality of AC6-deficient mice to the levels of wild-type mice. Furthermore, AC6-deficient mice lacked dDAVP-promoted inner medullary cAMP formation and phosphorylation of serine-269 and had attenuated increases in both phosphorylation of serine-256 and apical membrane AQP2 trafficking. In summary, AC6 expression determines inner medullary cAMP formation and AQP2 phosphorylation and trafficking, the absence of which causes nephrogenic diabetes insipidus.
authors.affiliation: Department of Medicine, Division of Nephrology/Hypertension, University of California San Diego and VA San Diego Healthcare System, 3350 La Jolla Village Drive (9151), San Diego, CA 92161, USA. trieg@ucsd.edu
authors.forename: Timo
authors.initials: T
authors.lastname: Rieg
authors.forename: Tong
authors.initials: T
authors.lastname: Tang
authors.forename: Fiona
authors.initials: F
authors.lastname: Murray
authors.forename: Jana
authors.initials: J
authors.lastname: Schroth
authors.forename: Paul A
authors.initials: PA
authors.lastname: Insel
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fenton
authors.forename: H Kirk
authors.initials: HK
authors.lastname: Hammond
authors.forename: Volker
authors.initials: V
authors.lastname: Vallon
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051399:Aquaporin 2 / Q000235:genetics / Q000378:metabolism*; D001127:Arginine Vasopressin / Q000378:metabolism; D015153:Blotting, Western; D000242:Cyclic AMP / Q000378:metabolism*; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D018500:Diabetes Insipidus, Nephrogenic / Q000503:physiopathology*; D004195:Disease Models, Animal; D007679:Kidney Medulla / Q000378:metabolism*; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009994:Osmolar Concentration; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D012680:Sensitivity and Specificity; D014868:Water Deprivation; D014882:Water-Electrolyte Balance / Q000502:physiology
chemical_list: D051399:Aquaporin 2; D012333:RNA, Messenger; D001127:Arginine Vasopressin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6; D003894:Deamino Arginine Vasopressin