Reciprocal regulation of aquaporin-2 abundance and degradation by protein kinase A and p38-MAP kinase.
Arginine-vasopressin (AVP) modulates the water channel aquaporin-2 (AQP2) in the renal collecting duct to maintain homeostasis of body water. AVP binds to vasopressin V2 receptors (V2R), increasing cAMP, which promotes the redistribution of AQP2 from intracellular vesicles into the plasma membrane. cAMP also increases AQP2 transcription, but whether altered degradation also modulates AQP2 protein levels is not well understood. Here, elevation of cAMP increased AQP2 protein levels within 30 minutes in primary inner medullary collecting duct (IMCD) cells, in human embryonic kidney (HEK) 293 cells ectopically expressing AQP2, and in mouse kidneys. Accelerated transcription or translation did not explain this increase in AQP2 abundance. In IMCD cells, cAMP inhibited p38-mitogen-activated protein kinase (p38-MAPK) via activation of protein kinase A (PKA). Inhibition of p38-MAPK associated with decreased phosphorylation (serine 261) and polyubiquitination of AQP2, preventing proteasomal degradation. Our results demonstrate that AVP enhances AQP2 protein abundance by altering its proteasomal degradation through a PKA- and p38-MAPK-dependent pathway.
Nedvetsky
Pavel I
PI
Leibniz-Institute for Molecular Pharmacology, Berlin, Germany. Pavel.Nedvetsky@ucsf.edu
Tabor
Vedrana
V
Tamma
Grazia
G
Beulshausen
Sven
S
Skroblin
Philipp
P
Kirschner
Aline
A
Mutig
Kerim
K
Boltzen
Mareike
M
Petrucci
Oscar
O
Vossenkämper
Anna
A
Wiesner
Burkhard
B
Bachmann
Sebastian
S
Rosenthal
Walter
W
Klussmann
Enno
E
D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism*; D001127:Arginine Vasopressin / Q000378:metabolism*; D002460:Cell Line; D005576:Colforsin; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006801:Humans; D007679:Kidney Medulla / Q000378:metabolism*; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis; D051381:Rats; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D051399:Aquaporin 2; D001127:Arginine Vasopressin; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex