Published online before print November 4, 2004, doi: 10.1161/01.RES.0000149570.20845.89
© 2004 American Heart Association, Inc.
Cellular Biology |
Hypertension-Linked Mutation in the Adducin 
-Subunit Leads to Higher AP2-µ2 Phosphorylation and Impaired Na+,K+-ATPase Trafficking in Response to GPCR Signals and Intracellular Sodium
From the Department of Medicine (R.T.K., G.O., A.M.B), Atherosclerosis Research Unit, Membrane Signaling Networks, Karolinska Institutet, Karolinska University Hospital, S-171 76 Stockholm, Sweden; the Department of Pharmacological and Pharmaceutical Sciences (R.E., C.H.P), College of Pharmacy, University of Houston, Tex; INSERM Unité 575 (J.Z.), Strasbourg, France; Prassis Research Institute Sigma-Tau (G.T.), Settimo Milanese, Italy; the Department of Medicine (A.I.K), University of Chicago, Ill; and Chair of Nephrology (G.B.), San Raffaele Hospital "Vita e Salute" University, Milan, Italy.
Correspondence to Dr Alejandro M. Bertorello, Department of Medicine, Atherosclerosis Research Unit, Karolinska University Hospital M1, S-171 76 Stockholm, Sweden. E-mail alejandro.bertorello{at}medks.ki.se
-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-µ2 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, µ2-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.
Key Words: high blood pressure • sodium retention • protein trafficking • cytoskeleton • endocytosis
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