In the adrenal cortex, production of glucocorticoids and mineralocorticoids is regulated by the differential zonal expression of two cytochrome P450 isozymes, CYP11B1 (11ß-hydroxylase), which is present in the zona fasciculata, and CYP11B2 (aldosterone synthase), which is restricted to the zona glomerulosa. These enzymes catalyze the final steps in the biosynthesis of cortisol and aldosterone, respectively. The most important regulators of CYP11B2 expression in zona glomerulosa (ZG) cells are angiotensin II and high plasma K⁺. Their effect is dependent on membrane depolarization and Ca²⁺ influx through voltage-dependent Ca²⁺ channels. Increased intracellular calcium activates CaM kinases, which activate expression of the CYP11B2 promoter via the phosphorylation of transcription factors of the CREB family and induction of the expression of factors of the NR4 subfamily of nuclear receptors (NGFI-B and Nurr1). However, very little is known about the upstream regulators restricting CYP11B2 expression to the zona glomerulosa. The basis for the unique sensitivity of ZG cells for plasma K⁺ concentration is a very high background K⁺ conductance, which is dependent on expression at high levels of two 2-pore domain (K2P) K⁺ channels, Task1 (KCNK3) and Task3 (KCNK9). Recent studies have shown that mice lacking Task1 (1) or both Task1 and Task3 (2) have primary hyperaldosteronism (PA), which is determined by different mechanisms. In Task1 null mice, hyperaldosteronism is present in young animals of either sex, but is corrected in males after puberty. Strikingly, in these animals hyperaldosteronism associates with abnormal adrenal cortex functional zonation, since Cyp11b2 is expressed in the inner region of the adrenal cortex and not in the glomerulosa. Significantly, hyperaldosteronism can be suppressed by dexamethasone administration. Additionally, this phenotype is under the control of sex hormones, as shown by the fact that castration of male Task1 -/- animals prevents normal Cyp11b2 distribution, while testosterone injection in female Task1 -/- mice restores expression of Cyp11b2 in ZG cells. Conversely, double Task1/Task3 -/- male mice fed either a low- or a high-sodium diet present milder PA, compared with female Task1 -/- mice, which is not sensitive to AT1 receptor blockade. Female double Task1 -/- Task3 -/- mice also display aberrant expression of Cyp11b2 in the inner region of the adrenal cortex, while Task3 -/- mice of either sex display normal expression of Cyp11b2 in zona glomerulosa. Together, these studies have shown the pivotal importance of TASK potassium channels in the regulation of aldosterone production in the adrenal cortex in vivo and have revealed an unexpected effect of Task1 upon the functional zonation of the adrenal cortex. Mutations or altered expression of TASK1 and TASK3 may then be implicated in forms of either familial or sporadic human PA. Moreover, the knowledge of the underlying molecular mechanisms involved in the development of an aberrant adrenal functional zonation and PA could allow to identify new therapeutic targets in this disease.

1-Heitzmann, D., R. Derand, et al. (2008). "Invalidation of TASK1 potassium channels disrupts adrenal gland zonation and mineralocorticoid homeostasis." Embo J, 27: 179–87.

2-Davies, L. A., C. Hu, et al. (2008). "TASK channel deletion in mice causes primary hyperaldosteronism." Proc Natl Acad Sci U S A, 105: 2203–2208