Calneuron 1 Increased Ca²⁺ in the Endoplasmic Reticulum and Aldosterone Production in Aldosterone-Producing AdenomaNovelty and Significance

We appreciate the chance to discuss the letter of Ravarotto et al regarding to our paper 1. They raise the issue of hyperparathyroidism secondary to increased calcium excretion in hyperaldosteronism 2 and its potential influence on intracellular Ca2+. Administration of aldosterone Na+ excess to rats increases urinary calcium, decreases serum Ca2+, increases parathyroid hormone, and increases cytosolic Ca2+ in the heart and other tissues 3. By extrapolation, cytosolic calcium in adrenal cells may also be increased, though this was not studied. Parathyroid hormone also increases angiotensin II- and potassium-stimulated aldosterone biosynthesis in bovine zona glomerulosa cells and produces a mild increase in cytosolic calcium 4. As Ravarotto, et al. stated, stored Ca2+ in endoplasmic reticulum (ER) is transferred to mitochondria, thus the ER network has a pivotal role in the maintenance of multiple vital Ca2+-dependent processes 5. Rapid release of Ca2+ from the ER results in transient Ca2+ increases in the mitochondria stimulates activity of the CYP11B2 enzyme in adrenal glomerulosa cells and has pro-survival effects 6-8. Excessive increases in mitochondrial Ca2+ concentration for a prolonged time induce the opening of the mitochondrial permeability transition pore, and induces apoptotic or necrotic cell death. Stored Ca2+ in ER is also released to the nuclei and cytosol 9. Our study focused on cytosolic Ca2+ and clarified that increased Ca2+ leads to a sequence of events that increase CYP11B2 transcription 1. This is compatible with data demonstrating that increased Ca2+ availability via the ER-mitochondria network and mitochondrial NADPH-Ca2+ stimulates CYP11B2 activity, resulting in aldosterone synthesis 6.
Thus, based on the results of our study, we suggest that increased CALN1 expression in APA is associated with elevated Ca2+ storage in ER, leading to a sequence of events that culminate in stimulating CYP11B2 transcription and aldosterone overproduction. Thus CALN1 would be a potential therapeutic target for excess of aldosterone production.

References
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