Many Channels Lead to Aldosterone☆

Commentary Aldosterone secretion is under the control of potassium, renin and angiotensin (Ang II). Consequently, concepts to explain autonomous al-dosterone secretion as the basis for primary aldosteronism (PA) included the presence of stimulating autoantibodies to the Ang II type 1 receptor (AT1R), gain-of-function mutations in the AT1R and aberrant expression of G-protein-coupled membrane receptors that are responsive to alternative stimuli and have access to the cellular AT1R signaling apparatus (Luft, 2013, Mazzuco et al., 2010). However, while these ideas are great the power to explaining the pathophysiology of PA remained small. The breakthrough came with the systematic clarification of sig-naling pathways which control aldosterone secretion, the application of whole exome sequencing to adrenal disease and the discovery that a mutated channel which is associated with familial and sporadic forms of PA results in an increase in intracellular calcium (Fig. 1) (Choi et al., 2011). The same group also discovered that a mutation in CACNA1H, encoding the voltage-gated T-type calcium channel Cav3.2, is associated with an early onset form of primary hyperaldosteronism (Scholl et al., 2015). The data in the EBioMedicine paper by Daniil et al. strongly supports the disease-driving character of such mutations allowing calcium to influx more readily into the aldosterone-producing adrenal zona glomerulosa cell. And the paper adds familial and sporadic variants of PA with altered CACNA1H sequence to our knowledge database (Daniil et al., 2016). Systematic clinical work and modern genetic analysis combined with an elegant set of molecular, cellular and electro-physiological experiments helped the group to visualize a genotype-phenotype relationship. This relationship was apparent in clinical observations and detectable by means of in vitro investigations into channel properties, calcium signaling, steroidogenic enzyme expression and aldosterone secretion into cell culture supernatants. While the patients with a mild mutation did not, the subject with the severe CACNA1H mutation had early onset PA and multiplex developmental disorder. Interestingly , pathological neurologic features had been reported to occur in patients with PA due to a CACNA1D mutation which is also known to strongly affect intracellular calcium within zona glomerulosa cells (Scholl et al., 2013). The tumors of such patients are comparably small but show strong expression of aldosterone synthase and suppression of renin. Interestingly, it was suggested that some mutations may severely interfere with the cellular calcium homeostasis and even cause the death of an affected adrenocortical cell thus preventing the cell from developing hyperplastic or tumorous tissue. However, less …