scholarly journals The Potassium Channel, Kir3.4 Participates in Angiotensin II-Stimulated Aldosterone Production by a Human Adrenocortical Cell Line

Endocrinology ◽  
2012 ◽  
Vol 153 (9) ◽  
pp. 4328-4335 ◽  
Author(s):  
Kenji Oki ◽  
Maria W. Plonczynski ◽  
Milay Luis Lam ◽  
Elise P. Gomez-Sanchez ◽  
Celso E. Gomez-Sanchez
Keyword(s):  
Cytochrome P450 ◽  
Angiotensin Ii ◽  
Potassium Channel ◽  
Intracellular Calcium ◽  
Regulatory Protein ◽  
Membrane Depolarization ◽  
Membrane Voltage ◽  
Aldosterone Secretion ◽  
Calmodulin Kinase ◽  
Kinase Cascade

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.

Electrical responses in cat adrenal cortex: possible relation to aldosterone secretion.

1979 ◽  
Vol 237 (2) ◽  
pp. E158 ◽  
Author(s):  
E Natke ◽  
E Kabela
Keyword(s):  
Membrane Potential ◽  
Angiotensin Ii ◽  
Adrenal Cortex ◽  
Adrenal Glands ◽  
Membrane Depolarization ◽  
Zona Glomerulosa ◽  
Membrane Potentials ◽  
Zona Fasciculata ◽  
Aldosterone Secretion ◽  
Stimulus Secretion Coupling

The effects of secretagogues for aldosterone release were studied on the membrane potential of cells in the adrenal cortex of the cat. Adrenal glands were excised, sliced, and continuously superfused. Membrane potentials were recorded from both zona glomerulosa and zona fasciculata-reticularis. Secretagogues, angiotensin II (1 microgram/ml) and 20 mM KCl, were found to depolarize cells rapidly. Ouabain (10(-5) M) also depolarized the membrane potential although the response was sluggish. Samples of the superfusate were collected and analyzed by radioimmunoassay for their aldosterone and cortisol content. Depolarizing concentrations of angiotensin II, KCl, and ouabain seemed to increase aldosterone release. Cortisol output was more variable. Saralasin blocked the effects of angiotensin II on the membrane potential. These experiments suggest that membrane depolarization plays a role in the stimulus-secretion coupling of mineral corticoids.

TREK-1 K+ channels couple angiotensin II receptors to membrane depolarization and aldosterone secretion in bovine adrenal glomerulosa cells

2004 ◽  
Vol 287 (6) ◽  
pp. E1154-E1165 ◽  
Author(s):  
Judith A. Enyeart ◽  
Sanjay J. Danthi ◽  
John J. Enyeart
Keyword(s):  
Membrane Potential ◽  
Angiotensin Ii ◽  
Adrenal Cortex ◽  
Receptor Activation ◽  
Membrane Depolarization ◽  
Resting Membrane Potential ◽  
Zona Fasciculata ◽  
Ang Ii ◽  
Aldosterone Secretion ◽  
Wide Range

Bovine adrenal glomerulosa (AZG) cells were shown to express bTREK-1 background K+ channels that set the resting membrane potential and couple angiotensin II (ANG II) receptor activation to membrane depolarization and aldosterone secretion. Northern blot and in situ hybridization studies demonstrated that bTREK-1 mRNA is uniformly distributed in the bovine adrenal cortex, including zona fasciculata and zona glomerulosa, but is absent from the medulla. TASK-3 mRNA, which codes for the predominant background K+ channel in rat AZG cells, is undetectable in the bovine adrenal cortex. In whole cell voltage clamp recordings, bovine AZG cells express a rapidly inactivating voltage-gated K+ current and a noninactivating background K+ current with properties that collectively identify it as bTREK-1. The outwardly rectifying K+ current was activated by intracellular acidification, ATP, and superfusion of bTREK-1 openers, including arachidonic acid (AA) and cinnamyl 1–3,4-dihydroxy-α-cyanocinnamate (CDC). Bovine chromaffin cells did not express this current. In voltage and current clamp recordings, ANG II (10 nM) selectively inhibited the noninactivating K+ current by 82.1 ± 6.1% and depolarized AZG cells by 31.6 ± 2.3 mV. CDC and AA overwhelmed ANG II-mediated inhibition of bTREK-1 and restored the resting membrane potential to its control value even in the continued presence of ANG II. Vasopressin (50 nM), which also physiologically stimulates aldosterone secretion, inhibited the background K+ current by 73.8 ± 9.4%. In contrast to its potent inhibition of bTREK-1, ANG II failed to alter the T-type Ca2+ current measured over a wide range of test potentials by using pipette solutions of identical nucleotide and Ca2+-buffering compositions. ANG II also failed to alter the voltage dependence of T channel activation under these same conditions. Overall, these results identify bTREK-1 K+ channels as a pivotal control point where ANG II receptor activation is transduced to depolarization-dependent Ca2+ entry and aldosterone secretion.

scholarly journals Minireview: Potassium Channels and Aldosterone Dysregulation: Is Primary Aldosteronism a Potassium Channelopathy?

Endocrinology ◽  
2014 ◽  
Vol 155 (1) ◽  
pp. 47-55 ◽  
Author(s):  
Celso E. Gomez-Sanchez ◽  
Kenji Oki
Keyword(s):  
Potassium Channel ◽  
Calcium Channel ◽  
G Protein ◽  
Primary Aldosteronism ◽  
Somatic Mutations ◽  
Membrane Depolarization ◽  
Zona Glomerulosa ◽  
Aldosterone Secretion ◽  
K Channels ◽  
Inward Rectifying Potassium Channel

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.

scholarly journals Angiotensin II and III Metabolism and Effects on Steroid Production in the HAC15 Human Adrenocortical Cell Line

Endocrinology ◽  
2013 ◽  
Vol 154 (1) ◽  
pp. 214-221 ◽  
Author(s):  
Kenji Oki ◽  
Phillip G. Kopf ◽  
William B. Campbell ◽  
Milay Luis Lam ◽  
Takeshi Yamazaki ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cell Line ◽  
Regulatory Protein ◽  
Renin Angiotensin System ◽  
Hydroxysteroid Dehydrogenase ◽  
Zona Glomerulosa ◽  
Cortisol Secretion ◽  
Adrenocortical Cell ◽  
Aldosterone Secretion ◽  
Steroidogenic Acute Regulatory

Aldosterone is synthesized in the zona glomerulosa of the adrenal cortex under primary regulation by the renin-angiotensin system. Angiotensin II (A-II) acts through the angiotensin types 1 and 2 receptors (AT1R and AT2R). A-II is metabolized in different tissues by various enzymes to generate two heptapeptides A-III and angiotensin 1-7, which can then be catabolized into smaller peptides. A-II was more potent than A-III in stimulating aldosterone secretion in the adrenocortical cell line HAC15, and A-II, but not A-III, stimulated cortisol secretion. A-II stimulated mRNA expression of steroidogenic acute regulatory protein, 3β-hydroxysteroid dehydrogenase, CYP11B1, and CYP11B2, whereas A-III stimulated 3β-hydroxysteroid dehydrogenase, CYP11B1, and CYP11B2 but decreased the expression of CYP17A1 required for cortisol synthesis. The stimulation of aldosterone secretion by A-II and A-III was blocked by the AT1R receptor blocker, losartan, but not by an AT2R blocker. A-II was rapidly metabolized by the HAC15 cells to mainly to angiotensin 1-7, but not to A-III, and disappeared from the supernatant within 6 h. A-III was metabolized rapidly and disappeared within 1 h. In conclusion, A-II was not converted to A-III in the HAC15 cell and is the more potent stimulator of aldosterone secretion and cortisol of the two. A-III stimulated aldosterone secretion but not cortisol secretion.

Renin-angiotensin system and aldosterone secretion during aortic constriction in the rat

1977 ◽  
Vol 232 (5) ◽  
pp. F434-F437 ◽  
Author(s):  
R. H. Freeman ◽  
J. O. Davis ◽  
W. S. Spielman
Keyword(s):  
Angiotensin Ii ◽  
Perfusion Pressure ◽  
Renin Angiotensin System ◽  
Renal Perfusion ◽  
Bilateral Nephrectomy ◽  
Aortic Constriction ◽  
Aldosterone Secretion ◽  
Experimental Conditions ◽  
Angiotensin System ◽  
Renin Angiotensin

Suprarenal aortic constriction sufficient to reduce renal perfusion pressure by approximately 50% increased aldosterone secretion in anesthetized rats pretreated with dexamethasone. Bilateral nephrectomy under the same experimental conditions blocked the aldosterone response. Additionally, [1-sarcosine, 8-alanine]angiotensin II blocked the response in aldosterone secretion to aortic constriction in dexamethasone-treated rats. Finally, in rats hypophysectomized to exclude the influence of ACTH, the aldosterone response to aortic constriction was blocked by [1-sarcosine, 8-alanine]angiotensin II. The results indicate that angiotensin II increased aldosterone secretion during aortic constriction in the rat. These observations, along with those reported previously in sodium-depleted rats, point to an important overall role for the renin-angiotensin system in the control of aldosterone secretion in the rat.

scholarly journals Angiotensin II-activated protein kinase D mediates acute aldosterone secretion

2010 ◽  
Vol 317 (1-2) ◽  
pp. 99-105 ◽  
Author(s):  
Brian A. Shapiro ◽  
Lawrence Olala ◽  
Senthil Nathan Arun ◽  
Peter M. Parker ◽  
Mariya V. George ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Kinase ◽  
Protein Kinase D ◽  
Aldosterone Secretion

scholarly journals Role of tyrosine kinase and protein kinase C in the steroidogenic actions of angiotensin II, α-melanocyte-stimulating hormone and corticotropin in the rat adrenal cortex

1995 ◽  
Vol 305 (2) ◽  
pp. 433-438 ◽  
Author(s):  
S Kapas ◽  
A Purbrick ◽  
J P Hinson
Keyword(s):  
Protein Kinase C ◽  
Angiotensin Ii ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Zona Glomerulosa ◽  
Aldosterone Secretion ◽  
Melanocyte Stimulating Hormone ◽  
Kinase C ◽  
Stimulating Hormone

The role of protein kinases in the steroidogenic actions of alpha-melanocyte-stimulating hormone (alpha-MSH), angiotensin II (AngII) and corticotropin (ACTH) in the rat adrenal zona glomerulosa was examined. Ro31-8220, a potent selective inhibitor of protein kinase C (PKC), inhibited both AngII- and alpha-MSH-stimulated aldosterone secretion but had no effect on aldosterone secretion in response to ACTH. The effect of Ro31-8220 on PKC activity was measured in subcellular fractions. Basal PKC activity was higher in cytosol than in membrane or nuclear fractions. Incubation of the zona glomerulosa with either alpha-MSH or AngII resulted in significant increases in PKC activity in the nuclear and cytosolic fractions and decreases in the membrane fraction. These effects were all inhibited by Ro31-8220. ACTH caused a significant increase in nuclear PKC activity only, and this was inhibited by Ro31-8220 without any significant effect on the steroidogenic response to ACTH, suggesting that PKC translocation in response to ACTH may be involved in another aspect of adrenal cellular function. Tyrosine phosphorylation has not previously been considered to be an important component of the response of adrenocortical cells to peptide hormones. Both AngII and alpha-MSH were found to activate tyrosine kinase, but ACTH had no effect, observations that have not been previously reported. Tyrphostin 23, a specific antagonist of tyrosine kinases, inhibited aldosterone secretion in response to AngII and alpha-MSH, but not ACTH. These data confirm the importance of PKC in the adrenocortical response to AngII and alpha-MSH, and, furthermore, indicate that tyrosine kinase may play a critical role in the steroidogenic actions of AngII and alpha-MSH in the rat adrenal zona glomerulosa.

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