Na/K Pump Mutations Associated with Primary Hyperaldosteronism Cause Loss of Function

Biochemistry
Dylan J MeyerPablo Artigas

Abstract

Primary hyperaldosteronism (Conn's syndrome), a common cause of secondary hypertension, is frequently produced by unilateral aldosterone-producing adenomas that carry mutations in ion-transporting genes, including ATP1A1, encoding the Na/K pump's α1 subunit. Whether Na/K pump mutant-mediated inward currents are required to depolarize the cell and increase aldosterone production remains unclear, as such currents were observed in four out of five mutants described so far. Here, we use electrophysiology and uptake of the K+ congener 86Rb+, to characterize the effects of eight additional Na/K pump mutations in transmembrane segments TM1 (delM102-L103, delL103-L104, and delM102-I106), TM4 (delI322-I325 and I327S), and TM9 (delF956-E961, delF959-E961, and delE960-L964), expressed in Xenopus oocytes. All deletion mutants induced abnormal inward currents of different amplitudes at physiological voltages, while I327S lacked such currents. A detailed functional characterization revealed that I327S significantly reduces intracellular Na+ affinity without altering affinity for external K+. 86Rb+-uptake experiments show that I327S dramatically impairs function under physiological concentrations of Na+ and K+. Since Na/K pumps in the adrenal...Continue Reading

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Citations

Aug 28, 2020·The Journal of Clinical Endocrinology and Metabolism·Kazutaka NanbaHironobu Sasano
Nov 25, 2020·The Journal of General Physiology·Dylan J MeyerPablo Artigas
Jul 8, 2021·American Journal of Physiology. Cell Physiology·Elisa D BiondoPablo Artigas

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