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Tauber, Philipp; Aichinger, B.; Christ, C.; Stindl, J.; Rhayem, Y.; Beuschlein, F.; Warth, R.; Bandulik, S. (2016): Cellular Pathophysiology of an Adrenal Adenoma-Associated Mutant of the Plasma Membrane Ca²⁺-ATPase ATP2B3. In: Endocrinology, Vol. 157, Nr. 6: S. 2489-2499
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Abstract

Adrenal aldosterone-producing adenomas (APAs) are a main cause for primary aldosteronism leading to arterial hypertension. Physiologically, aldosterone production in the adrenal gland is stimulated by angiotensin II and high extracellular potassium. These stimuli lead to a depolarization of the plasma membrane and, as a consequence, an increase of intracellular Ca2+. Mutations of the plasma membrane Ca2+-ATPase ATP2B3 have been found in APAs with a prevalence of 0.6%-3.1%. Here, we investigated the effects of the APA-associated ATP2B3(Leu425_Val426del) mutation in adrenocortical NCI-H295R and human embryonic kidney (HEK-293) cells. Ca2+ measurements revealed a higher basal Ca2+ level in cells expressing the mutant ATP2B3. This rise in intracellular Ca2+ was even more pronounced under conditions with high extracellular Ca2+ pointing to an increased Ca2+ influx associated with the mutated protein. Furthermore, cells with the mutant ATP2B3 appeared to have a reduced capacity to export Ca2+ suggesting a loss of the physiological pump function. Surprisingly, expression of the mutant ATP2B3 caused a Na+-dependent inward current that strongly depolarized the plasma membrane and compromised the cytosolic cation composition. In parallel to these findings, mRNA expression of the cytochrome P450, family 11, subfamily B, polypeptide 2 (aldosterone synthase) was substantially increased and aldosterone production was enhanced in cells overexpressing mutant ATP2B3. In summary, the APA-associated ATP2B3(Leu425_Val426del) mutant promotes aldosterone production by at least 2 different mechanisms: 1) a reduced Ca2+ export due to the loss of the physiological pump function;and 2) an increased Ca2+ influx due to opening of depolarization-activated Ca2+ channels as well as a possible Ca2+ leak through the mutated pump.