Na/K Pump Mutations Associated with Primary Hyperaldosteronism Cause Loss of Function
2019
Meyer, Dylan J. | Gatto, Craig | Artigas, Pablo
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 cortex may be formed by association of α1 with β3 instead of β1 subunits, we evaluated whether G99R (another mutant without inward currents when associated with β1) would show inward currents when associated with β3. We found that the kinetic characteristics of either mutant or wild-type α1β3 pumps expressed in Xenopus oocytes to be indistinguishable from those of α1β1 pumps. The observed functional consequences of each hyperaldosteronism mutant point to the loss of Na/K pump function as the common feature of all mutants, which is sufficient to induce hyperaldosteronism.
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