Hypertension-linked mutation in the adducin alpha-subunit leads to higher AP2-mu2 phosphorylation and impaired Na+,K+-ATPase trafficking in response to GPCR signals and intracellular sodium.
Alpha-adducin polymorphism in humans is associated with abnormal renal sodium handling and high blood pressure. The mechanisms by which mutations in adducin affect the renal set point for sodium excretion are not known. Decreases in Na+,K+-ATPase activity attributable to endocytosis of active units in renal tubule cells by dopamine regulates sodium excretion during high-salt diet. Milan rats carrying the hypertensive adducin phenotype have a higher renal tubule Na+,K+-ATPase activity, and their Na+,K+-ATPase molecules do not undergo endocytosis in response to dopamine as do those of the normotensive strain. Dopamine fails to promote the interaction between adaptins and the Na+,K+-ATPase because of adaptin-mu2 subunit hyperphosphorylation. Expression of the hypertensive rat or human variant of adducin into normal renal epithelial cells recreates the hypertensive phenotype with higher Na+,K+-ATPase activity, mu2-subunit hyperphosphorylation, and impaired Na+,K+-ATPase endocytosis. Thus, increased renal Na+,K+-ATPase activity and altered sodium reabsorption in certain forms of hypertension could be attributed to a mutant form of adducin that impairs the dynamic regulation of renal Na+,K+-ATPase endocytosis in response to natriuretic signals.
Efendiev
Riad
R
Department of Medicine, Atherosclerosis Research Unit, Membrane Signaling Networks, Karolinska Institutet, Karolinska University Hospital, S-171 76 Stockholm, Sweden.
Krmar
Rafael T
RT
Ogimoto
Goichi
G
Zwiller
Jean
J
Tripodi
Grazia
G
Katz
Adrian I
AI
Bianchi
Giuseppe
G
Pedemonte
Carlos H
CH
Bertorello
Alejandro M
AM
D033962:Adaptor Protein Complex 2 / Q000737:chemistry / Q000378:metabolism*; D033983:Adaptor Protein Complex mu Subunits / Q000737:chemistry / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D002460:Cell Line / Q000187:drug effects / Q000201:enzymology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology*; D004298:Dopamine / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000201:enzymology; D004848:Epithelium / Q000201:enzymology; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D007684:Kidney Tubules / Q000187:drug effects / Q000201:enzymology*; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D009318:Natriuresis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009893:Opossums; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D025941:Protein Interaction Mapping; D021122:Protein Subunits; D051381:Rats; D011922:Rats, Mutant Strains; D011993:Recombinant Fusion Proteins / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014162:Transfection; D000099291:Adducins
D033962:Adaptor Protein Complex 2; D033983:Adaptor Protein Complex mu Subunits; D003598:Cytoskeletal Proteins; D004298:Dopamine; D008840:Microfilament Proteins; D010749:Phosphoprotein Phosphatases; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D000254:Sodium-Potassium-Exchanging ATPase; C501062:ADD2 protein, human; D000099291:Adducins; C501061:Add2 protein, rat; C438886:adaptor protein complex 2, mu 2 subunit; C498532:Atp1a2 protein, rat