Expression of a dominant negative Protein Kinase A (PKA) mutation in kidney elicits a XXXX phenotype.

@entity2011 @entity2700 @entity21515 @entity19 @entity4683 @entity59721 @entity61376 @entity2010
UNASSIGNED: PKA plays a critical role in water excretion through regulation of the production and action of the antidiuretic hormone, arginine vasopressin (AVP). The AVP prohormone is produced in the hypothalamus where its transcription is regulated by cAMP. Once released into circulation, AVP stimulates antidiuresis through activation of vasopressin 2 receptors ( @entity59721 ) in renal principal cells. V2R activation increases cAMP and activates PKA, which in turn phosphorylates @entity21515 , triggering apical membrane accumulation, increased collecting duct permeability and water reabsorption. We used @entity61376 -Cre-mediated expression of a dominant-negative PKA regulatory subunit (RIaB) to disrupt kinase activity in vivo and assess the role of PKA in fluid homeostasis. RIaB expression gave rise to marked @entity4683 and @entity2011 ; however, neither hypothalamic Avp mRNA expression nor urinary AVP levels were attenuated, indicating a primary physiological effect on the kidney. RIaB @entity19 displayed a marked deficit in urinary concentrating ability and greatly reduced levels of @entity21515 and phospho- @entity21515 . @entity2700 induced @entity21515 mRNA in the kidney of both control and RIaB-expressing @entity19 , but @entity21515 protein levels were still reduced in RIaB-expressing mutants and the @entity19 are unable to fully concentrate their urine and conserve water. We conclude that partial PKA inhibition in kidney leads to post-translational effects that reduce @entity21515 protein levels, and interfere with apical membrane localization. These findings demonstrate a distinct physiological role for PKA signaling in both short- and long-term regulation of @entity21515 and characterize a novel @entity19 model of @entity2010 .
