On the effect of hyperaldosteronism-inducing mutations in Na/K pumps

Abstract

Mutated Na/K pumps in adrenal adenomas are thought to cause hyperaldosteronism via a gain-of-function effect involving a depolarizing inward current. The findings of Meyer et al. suggest instead that the common mechanism by which Na/K pump mutants lead to hyperaldosteronism is a loss-of-function.

Functional consequences of the CAPOS mutation E818K of Na+,K+-ATPase

“…The leak current is also increased by ␣2 Na ϩ ,K ϩ -ATPase C-terminal mutations causing familial hemiplegic migraine (36), as well as by C-terminal deletions (37,38), and certain mutations causing aldosterone producing adenomas (39). An increased leak current might represent a gain of function with dominant-negative effect leading to disease (33), because the leak current in principle could cause depolarization of the neuron, although it has been questioned whether the magnitude of the measured current is sufficient to cause significant cell depolarization (40). In contrast to the reports on an enhanced leak current being associated with disease, the AHC mutation E815K has been found to diminish the proton leak current, and a disturbance of pH regulation and consequent intracellular alkalization might therefore be part of the pathophysiology caused by E815K (29).…”

Subtle mutation, far-reaching effects

“…However, when mutations of the Na + ,K + -ATPase are the initiators, it must be an indirect way that triggers the gain of intracellular Ca 2+ . But even if one restricts the investigation to the Na + ,K + -ATPase, it turns out that the underlying molecular mechanism is not just one clear-cut process, as it is revealed in the paper of Meyer et al (2017) .…”

“…To shed light on the pathways of the ions leaking through the mutated Na + ,K + -ATPase and to find out by which mechanism they may cause the increased Ca 2+ concentration that triggers the autonomous hypersecretion of aldosterone, Meyer et al (2017) set up an elaborate experimental approach. In their survey, the five mutants of the human Na + ,K + -ATPase were expressed in Xenopus oocytes, and the pump-induced electric currents were measured by the two-electrode voltage clamp technique.…”

“…When Meyer et al (2017) studied the EETA963S mutant in detail, they found that, at physiological salt concentrations (i.e., 125 mM Na + o and 4.5 mM K + o ), the leak inward current disappeared completely at a membrane voltage of −50 mV. Bearing in mind that cells exhibit monoallelic mutations in aldosterone-producing adenomas ( Beuschlein et al, 2013 ), so that only 50% of the expressed Na + ,K + -ATPases are mutated, it is reasonable to conclude the following: If half of the pumps generate the normal outward current and these mutated pumps do not generate significant inward leak currents, it is unlikely that such a condition causes a membrane depolarization large enough to trigger an autonomous hypersecretion of aldosterone.…”

“…Only the ion-binding affinities for Na + and K + were reduced in both conformations of the pump when compared with the wild-type Na + ,K + -ATPase. Meyer et al (2017) summarized that the observed changes in the G99R mutant “induce a major loss-of-function under physiological conditions.”…”