Minireview: potassium channels and aldosterone dysregulation: is primary aldosteronism a potassium channelopathy?

Abstract

Primary aldosteronism is the most common form of secondary hypertension and has significant cardiovascular consequences. Aldosterone-producing adenomas (APAs) are responsible for half the cases of primary aldosteronism, and about half have mutations of the G protein-activated inward rectifying potassium channel Kir3.4. Under basal conditions, the adrenal zona glomerulosa cells are hyperpolarized with negative resting potentials determined by membrane permeability to K(+) mediated through various K(+) channels, including the leak K(+) channels TASK-1, TASK-3, and Twik-Related Potassium Channel 1, and G protein inward rectifying potassium channel Kir3.4. Angiotensin II decreases the activity of the leak K(+) channels and Kir3.4 channel and decreases the expression of the Kir3.4 channel, resulting in membrane depolarization, increased intracellular calcium, calcium-calmodulin pathway activation, and increased expression of cytochrome P450 aldosterone synthase (CYP11B2), the last enzyme for aldosterone production. Somatic mutations of the selectivity filter of the Kir3.4 channel in APA results in loss of selectivity for K(+) and entry of sodium, resulting in membrane depolarization, calcium mobilization, increased CYP11B2 expression, and hyperaldosteronism. Germ cell mutations cause familial hyperaldosteronism type 3, which is associated with adrenal zona glomerulosa hyperplasia, rather than adenoma. Less commonly, somatic mutations of the sodium-potassium ATPase, calcium ATPase, or the calcium channel calcium channel voltage-dependent L type alpha 1D have been found in some APAs. The regulation of aldosterone secretion is exerted to a significant degree by activation of membrane K(+) and calcium channels or pumps, so it is not surprising that the known causes of disorders of aldosterone secretion in APA have been channelopathies, which activate mechanisms that increase aldosterone synthesis.

• Authors: Celso E Gomez-Sanchez, Kenji Oki
• Journal: Endocrinology (Endocrinology) Vol. 155 Issue 1 Pg. 47-55 (Jan 2014) ISSN: 1945-7170 [Electronic] United States
• PMID: 24248457 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S., Review)

Chemical References

• G Protein-Coupled Inwardly-Rectifying Potassium Channels
• Kcnj5 protein, mouse
• Potassium Channels
• Steroids
• Aldosterone
• Potassium
• Calcium

Topics

• Adrenal Glands (metabolism)
• Aldosterone (metabolism)
• Animals
• Calcium (metabolism)
• Cell Membrane (metabolism)
• Channelopathies (genetics, metabolism)
• G Protein-Coupled Inwardly-Rectifying Potassium Channels (metabolism)
• HEK293 Cells
• Humans
• Hyperaldosteronism (metabolism, pathology)
• Mice
• Mice, Transgenic
• Potassium (chemistry)
• Potassium Channels (metabolism)
• Signal Transduction
• Steroids (metabolism)
• Zona Glomerulosa (metabolism)