Subtle mutation, far-reaching effects

Abstract

Insufficient sodium-ion extrusion by mutated Na⁺,K⁺-ATPases causes hyperaldosteronism.

Figure 1.

Aldosterone production in cells of the adrenal gland. (A) Under nonpathological conditions, the intracellular Na⁺ concentration is maintained low by an adequate Na⁺ extrusion capacity provided by wild-type Na⁺,K⁺-ATPases. This allows for proper calcium extrusion by the Na/Ca exchanger (NCX). Physiological depolarizing fluctuations of the membrane potential lead to transient openings of Ca channels, and a temporarily enhanced Ca²⁺ concentration provokes aldosterone production satisfying the aldosterone requirements of the organism. (B) In specific aldosterone-producing adenomas, expression of (monoallelic) mutant Na/K pumps reduces the Na⁺ extrusion performance to ∼50% and adds inward leaking Na⁺ currents (except in the case of the G99R mutant). The arrows through each “pump” insinuate the relative sizes and directions of the ouabain-sensitive currents. The pump malfunctions elevate the intracellular Na⁺ concentration, leading to reduced Ca²⁺ extrusion by NCX and, consequently, to increased intracellular Ca²⁺ concentrations. Elevated intracellular Ca²⁺ (as secondary messenger) increases StAR-dependent cholesterol transport in the mitochondria (the early step of aldosterone synthesis) and transcription of CYP11B2 (i.e., aldosterone synthase; the late step of synthesis), leading to a sustained production of aldosterone. Not included in both schemes are the numerous secondary-active transporters that use the inward directed electrochemical potential gradient of Na⁺ to transport other substrates needed in the cell metabolism on expense of further Na⁺ inward currents that are compensated entirely by the wild-type Na⁺,K⁺-ATPase under nonpathological conditions. (The schemes are derived from a slide presented by D. Meyer.)