Two-pore domain potassium channels in the adrenal cortex

Abstract

The physiological control of steroid hormone secretion from the adrenal cortex depends on the function of potassium channels. The "two-pore domain K(+) channels" (K2P) TWIK-related acid sensitive K(+) channel 1 (TASK1), TASK3, and TWIK-related K(+) channel 1 (TREK1) are strongly expressed in adrenocortical cells. They confer a background K(+) conductance to these cells which is important for the K(+) sensitivity as well as for angiotensin II and adrenocorticotropic hormone-dependent stimulation of aldosterone and cortisol synthesis. Mice with single deletions of the Task1 or Task3 gene as well as Task1/Task3 double knockout mice display partially autonomous aldosterone synthesis. It appears that TASK1 and TASK3 serve different functions: TASK1 affects cell differentiation and prevents expression of aldosterone synthase in the zona fasciculata, while TASK3 controls aldosterone secretion in glomerulosa cells. TREK1 is involved in the regulation of cortisol secretion in fasciculata cells. These data suggest that a disturbed function of K2P channels could contribute to adrenocortical pathologies in humans.

Fig. 1

Simplified models for the regulation of aldosterone synthesis in zona glomerulosa cells (a) and of cortisol synthesis in zona fasciculata cells (b). a Stimulatory action of Ang-II and increased plasma K⁺ concentration on aldosterone synthesis depends on membrane voltage depolarization and on increased cytosolic Ca²⁺. G-Protein-dependent activation of phospholipase-C (PLC-ß) via binding of Ang-II to angiotensin receptor 1 (AT1) leads to generation of inositol-triphosphate (IP₃) and diacylglycerol (DAG). IP₃ stimulates Ca²⁺ store release from the endoplasmatic reticulum (ER). DAG-dependent inhibition of TASK1 and TASK3 K⁺ channels or a high K⁺-induced shift of the Nernst potential depolarize the membrane. The depolarization activates voltage-dependent Ca²⁺ channels. Ca²⁺-calmodulin activates CaM-Kinases, and this leads to activation of transcription factors (TFs) and increased transcription of CYP11B2 (aldosterone synthase). MaxiK K⁺ channels are activated by the atrial natriuretic peptide (ANP), which binds to the natriuretic peptide receptor (NPR), or by increases of cytosolic Ca²⁺. MaxiK channels repolarize glomerulosa cells and decrease aldosterone synthesis. KCNJ5 K⁺ channels are highly expressed in human glomerulosa cells, but seem to be inactive under control conditions. b The stimulatory effect of ACTH on cortisol synthesis depends on cAMP-dependent signaling, but also involves membrane depolarization and increased cytosolic Ca²⁺. ACTH binds to the melanocortic-2-receptor (MC2R) and leads to activation of a G_αs-protein that stimulates adenylate cyclase (AC). cAMP-activated protein kinase A (PKA) activates transcription factors (TFs) inducing transcription of steroidogenic enzymes. These enzymes are required for cortisol synthesis (e.g., CHE: cholesterolester hydrolase, StAR: steroidogenic acute regulated protein, CYP17A1, CYP11B1). PKA also inhibits TREK1 K⁺ channels, depolarizes the membrane and promotes Ca²⁺ influx and consecutive activation of transcription factors. TREK1 is also inhibited by Ang-II. Additionally, TASK1 and Kv1.4 K⁺ channels are expressed in fasciculata cells