The potassium channel, Kir3.4 participates in angiotensin II-stimulated aldosterone production by a human adrenocortical cell line.
Angiotensin II (A-II) regulation of aldosterone secretion is initiated by inducing cell membrane depolarization, thereby increasing intracellular calcium and activating the calcium calmodulin/calmodulin kinase cascade. Mutations in the selectivity filter of the KCNJ5 gene coding for inward rectifying potassium channel (Kir)3.4 has been found in about one third of aldosterone-producing adenomas. These mutations result in loss of selectivity of the inward rectifying current for potassium, which causes membrane depolarization and opening of calcium channels and activation of the calcium calmodulin/calmodulin kinase cascade and results in an increase in aldosterone secretion. In this study we show that A-II and a calcium ionophore down-regulate the expression of KCNJ5 mRNA and protein. Activation of Kir3.4 by naringin inhibits A-II-stimulated membrane voltage and aldosterone secretion. Overexpression of KCNJ5 in the HAC15 cells using a lentivirus resulted in a decrease in membrane voltage, intracellular calcium, expression of steroidogenic acute regulatory protein, 3-β-hydroxysteroid dehydrogenase 3B2, cytochrome P450 11B1 and cytochrome P450 11B2 mRNA, and aldosterone synthesis. In conclusion, A-II appears to stimulate aldosterone secretion by depolarizing the membrane acting in part through the regulation of the expression and activity of Kir3.4.
Research and Medicine Services, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, 1500 East Woodrow Wilson Drive, Jackson, Mississippi 39216, USA.
Kenji
K
Oki
Maria W
MW
Plonczynski
Milay Luis
ML
Lam
Elise P
EP
Gomez-Sanchez
Celso E
CE
Gomez-Sanchez
D000450:Aldosterone / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology*; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D044950:Flavanones / Q000494:pharmacology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction
D044950:Flavanones; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; D000804:Angiotensin II; D000450:Aldosterone; C005274:naringin