The role of TASK1 in aldosterone production and its expression in normal adrenal and aldosterone-producing adenomas.
OBJECTIVE
Aldosterone production in the adrenal glomerulosa is mainly regulated by angiotensin II and K+. Adrenal glomerulosa cells are uniquely sensitive to extracellular K+. Genetic deletion of subunits of K+-selective leak-channels (KCNK), TASK1 and/or TASK3, in mice generates animals with hyperaldosteronism and histological changes in the adrenal cortex. Herein, we studied the expression of TASK1 in human adrenocortical cells, as well as its role in aldosterone production in H295R cells.


METHODS
TASK1 expression was investigated by comparative microarray analysis of aldosterone-producing adenomas (APA) and normal adrenals (NAs). The effects of TASK1 knockdown by siRNA transfection were investigated in H295R cells. Fluo-4 fluorescent measurements of intracellular Ca2+ and pharmacological inhibition of Ca2+ -dependent calmodulin kinases (CaMK) were performed to better define the effects of TASK1 on Ca2+ signalling pathways.


RESULTS
Microarray analysis of APA and NA showed similar expression of TASK1 between these two groups. However, in APA, NA and H295R cells the expression of TASK1 was predominant when compared with other KCNK family members. Knockdown of TASK1 (with siRNA) induced the expression of steroidogenic acute regulatory (StAR) protein and aldosterone synthase (CYP11B2), and also stimulated pregnenolone and aldosterone production. Cells transfected with siTASK1 had increased intracellular Ca2+, leading to activation of CaMK and increased expression of CYP11B2.


CONCLUSIONS
Our study reveals the predominant expression of TASK1 over other KCNK family genes in the human adrenal cortex. Herein, we also described the role of TASK1 in the regulation of human aldosterone production through regulation of intracellular Ca2+ and CaMK signalling pathways.
Nogueira
Edson F
EF
Department of Physiology, Medical College of Georgia, Augusta, GA 30912, USA.
Gerry
Daniel
D
Mantero
Franco
F
Mariniello
Barbara
B
Rainey
William E
WE
D000236:Adenoma / Q000378:metabolism*; D000310:Adrenal Gland Neoplasms / Q000378:metabolism; D000311:Adrenal Glands / Q000378:metabolism*; D000328:Adult; D000450:Aldosterone / Q000096:biosynthesis*; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000502:physiology*; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D015384:Zona Glomerulosa / Q000378:metabolism
C109137:KCNK1 protein, human; C486372:Kcnk1 protein, mouse; D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; D034741:RNA, Small Interfering; C420132:potassium channel subfamily K member 3; D000450:Aldosterone; D017871:Calcium-Calmodulin-Dependent Protein Kinases