scholarly journals L- and T-type calcium channels control aldosterone production from human adrenals

2020 ◽  
Vol 244 (1) ◽  
pp. 237-247 ◽  
Author(s):  
Tingting Yang ◽  
Min He ◽  
Hailiang Zhang ◽  
Paula Q Barrett ◽  
Changlong Hu
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Specific Inhibitor ◽  
Inhibitory Effect ◽  
Zona Glomerulosa ◽  
Aldosterone Secretion ◽  
Low Concentrations ◽  
Aldosterone Production ◽  
Aldosterone Producing Adenoma ◽  
Regulation Of Blood Pressure

Aldosterone, which plays a key role in the regulation of blood pressure, is produced by zona glomerulosa (ZG) cells of the adrenal cortex. Exaggerated overproduction of aldosterone from ZG cells causes primary hyperaldosteronism. In ZG cells, calcium entry through voltage-gated calcium channels plays a central role in the regulation of aldosterone secretion. Previous studies in animal adrenals and human adrenal adrenocortical cell lines suggest that the T-type but not the L-type calcium channel activity drives aldosterone production. However, recent clinical studies show that somatic mutations in L-type calcium channels are the second most prevalent cause of aldosterone-producing adenoma. Our objective was to define the roles of T and L-type calcium channels in regulating aldosterone secretion from human adrenals. We find that human adrenal ZG cells mainly express T-type CaV3.2/3.3 and L-type CaV1.2/1.3 calcium channels. TTA-P2, a specific inhibitor of T-type calcium channel subtypes, reduced basal aldosterone secretion from acutely prepared slices of human adrenals. Surprisingly, nifedipine, the prototypic inhibitor of L-type calcium channels, also decreased basal aldosterone secretion, suggesting that L-type calcium channels are active under basal conditions. In addition, TTA-P2 or nifedipine also inhibited aldosterone secretion stimulated by angiotensin II- or elevations in extracellular K+. Remarkably, blockade of either L- or T-type calcium channels inhibits basal and stimulated aldosterone production to a similar extent. Low concentrations of TTA-P2 and nifedipine showed additive inhibitory effect on aldosterone secretion. We conclude that T- and L-type calcium channels play equally important roles in controlling aldosterone production from human adrenals.

Effect of CO2/pH on the aldosterone response to hypoxia in bovine adrenal cells in vitro

1993 ◽  
Vol 265 (4) ◽  
pp. R820-R825
Author(s):  
H. Raff ◽  
B. Jankowski
Keyword(s):  
Respiratory Acidosis ◽  
Inhibitory Effect ◽  
Zona Glomerulosa ◽  
Ang Ii ◽  
Adrenal Cells ◽  
Aldosterone Production ◽  
Per Se ◽  
Air Control

Acidosis increases and hypoxia decreases aldosterone production from the adrenal zona glomulerosa in vivo, in situ, and in vitro. These effects appear to be located at different steps in the steroidogenic process. Because respiratory acidosis and hypoxemia are common sequelae of chronic lung disease, the present experiments evaluated the interaction of hypoxia and CO2 (with uncompensated or compensated extracellular pH) on aldosteronogenesis in vitro. Bovine adrenal zona glomerulosa cells were stimulated with angiotensin II (ANG II) or adenosine 3',5'-cyclic monophosphate under room air control (21% O2-0% CO2), CO2 per se (21% O2-10% CO2), hypoxia per se (10% O2-0% CO2), and the combination of CO2 and hypoxia (10% O2-10% CO2). Furthermore, under CO2, pH was either allowed to decrease from 7.2 to 6.8 (uncompensated) or its decrease was minimized (> 7.05) with NaOH (compensated). CO2 without pH compensation led to a significant increase in ANG II-stimulated aldosterone release; when the decrease in pH was minimized, CO2 inhibited ANG II-stimulated aldosterone release. Hypoxia inhibited aldosterone release; the inhibitory effect of hypoxia predominated when combined with CO2. In the presence of cyanoketone, pregnenolone production from endogenous precursors (early pathway) was unaffected. However, the conversion of corticosterone to aldosterone (late pathway) was inhibited by low O2 but unaffected by CO2. It is concluded that the inhibitory effect of low O2 on the late pathway predominates over the effects of uncompensated or compensated simulated respiratory acidosis on aldosteronogenesis.

scholarly journals Inhibition of L-type calcium-channel activity by thapsigargin and 2,5-t-butylhydroquinone, but not by cyclopiazonic acid

1994 ◽  
Vol 302 (1) ◽  
pp. 147-154 ◽  
Author(s):  
E J Nelson ◽  
C C R Li ◽  
R Bangalore ◽  
T Benson ◽  
R S Kass ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Cyclopiazonic Acid ◽  
Calcium Currents ◽  
Pituitary Cells ◽  
Channel Activity ◽  
Patch Clamp Technique ◽  
Channel Current ◽  
Low Concentrations ◽  
Ic50 Values

Thapsigargin (TG), 2,5-t-butylhydroquinone (tBHQ) and cyclopiazonic acid (CPA) all inhibit the initial Ca(2+)-response to thyrotropin-releasing hormone (TRH) by depleting intracellular Ca2+ pools sensitive to inositol 1,4,5-trisphosphate (IP3). Treatment of GH3 pituitary cells for 30 min with 5 nM TG, 500 nM tBHQ or 50 nM CPA completely eliminated the TRH-induced spike in intracellular free Ca2+ ([Ca2+]i). Higher concentrations of TG and tBHQ, but not CPA, were also found to inhibit strongly the activity of L-type calcium channels, as measured by the increase in [Ca2+]i or 45Ca2+ influx stimulated by depolarization. TG and tBHQ blocked high-K(+)-stimulated 45Ca2+ uptake, with IC50 values of 10 and 1 microM respectively. Maximal inhibition of L-channel activity was achieved 15-30 min after drug addition. Inhibition by tBHQ was reversible, whereas inhibition by TG was not. TG and CPA did not affect spontaneous [Ca2+]i oscillations when tested at concentrations adequate to deplete the IP3-sensitive Ca2+ pool. However, 20 microM TG and 10 microM tBHQ blocked [Ca2+]i oscillations completely. The effect of drugs on calcium currents was measured directly by using the patch-clamp technique. When added to the external bath, 10 microM CPA caused a sustained increase in the calcium-channel current amplitude over 8 min, 10 microM tBHQ caused a progressive inhibition, and 10 microM TG caused an enhancement followed by a sustained block of the calcium current over 8 min. In summary, CPA depletes IP3-sensitive Ca2+ stores and does not inhibit voltage-operated calcium channels. At sufficiently low concentrations, TG depletes IP3-sensitive stores without inhibiting L-channel activity, but, for tBHQ, inhibition of calcium channels occurs at concentrations close to those needed to block agonist mobilization of intracellular Ca2+.

scholarly journals Aldosterone secretion in patients with septic shock: a prospective study

2013 ◽  
Vol 57 (8) ◽  
pp. 636-641 ◽  
Author(s):  
Rafael Barberena Moraes ◽  
Gilberto Friedman ◽  
Marina Verçoza Viana ◽  
Tiago Tonietto ◽  
Henrique Saltz ◽  
...  
Keyword(s):  
Septic Shock ◽  
Serum Levels ◽  
Zona Glomerulosa ◽  
High Dose ◽  
Zona Fasciculata ◽  
Cortisol Secretion ◽  
Aldosterone Secretion ◽  
Acth Stimulation ◽  
Aldosterone Production ◽  
A Prospective Study

OBJECTIVE: To assess serum levels of the main factors that regulate the activation of the zona glomerulosa and aldosterone production in patients with septic shock, as well as their response to a high-dose (250 µg) adrenocorticotropic hormone (ACTH) stimulation test. SUBJECTS AND METHODS: In 27 patients with septic shock, baseline levels of aldosterone, cortisol, ACTH, renin, sodium, potassium, and lactate were measured, followed by a cortrosyn test. RESULTS: Renin correlated with baseline aldosterone and its variation after cortrosyn stimulation. Baseline cortisol and its variation did not correlate with ACTH. Only three patients had concomitant dysfunction of aldosterone and cortisol secretion. CONCLUSIONS: Activation of the zona glomerulosa and zona fasciculata are independent. Aldosterone secretion is dependent on the integrity of the renin-angiotensin-aldosterone system, whereas cortisol secretion does not appear to depend predominantly on the hypothalamic-pituitary-adrenal axis. These results suggest that activation of the adrenal gland in critically ill patients occurs by multiple mechanisms.

Effects of corticostatin-I on rat adrenal cells in vitro

1990 ◽  
Vol 125 (2) ◽  
pp. 287-292 ◽  
Author(s):  
T. Tominaga ◽  
J. Fukata ◽  
Y. Naito ◽  
Y. Nakai ◽  
S. Funakoshi ◽  
...  
Keyword(s):  
Specific Binding ◽  
Corticosterone Level ◽  
Inhibitory Effect ◽  
Zona Glomerulosa ◽  
Dependent Manner ◽  
Minimum Effective Concentration ◽  
Adrenal Cells ◽  
Aldosterone Production ◽  
The Media

ABSTRACT We have examined the mechanism by which corticostatin-I (CS-I) acts to attenuate ACTH-induced steroidogenesis in rat adrenal cells. CS-I inhibited ACTH-induced corticosterone production in a dosedependent manner, without any effects on the basal corticosterone level in adrenal cells. When the cells were stimulated by 100 pg ACTH/ml, the minimum effective concentration of CS-I was 100 ng/ml, and 0.3–1.0 μg CS-I/ml produced a 50% reduction of the stimulated corticosterone production. The inhibitory effect of CS-I on ACTH-stimulated corticosterone production became apparent within 15 min of incubation, and the effect was reversed quickly by the removal of CS-I from the media. CS-I had no effect on angiotensin II-stimulated aldosterone production by adrenal zona glomerulosa cells. CS-I also did not affect cyclic AMP- or forskolin-stimulated corticosterone production. In an in-vitro binding study using 125I-labelled CS-I, CS-I showed considerable specific binding to rat adrenal cells, and the binding competed with ACTH in a dose-dependent manner. These experiments suggest that CS-I competes with ACTH on their binding sites and exerts an inhibitory effect on the adrenal cells. Journal of Endocrinology (1990) 125, 287–292

scholarly journals OR24-03 GRK2 Mediates Beta-Adrenergic Receptor Crosstalk to Enhanced Adrenocortical AngII-Dependent Aldosterone Production

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Anastasios Lymperopoulos ◽  
Celina M Pollard ◽  
Janelle M Pereyra ◽  
Victoria L Desimine ◽  
Shelby L Wertz ◽  
...  
Keyword(s):  
G Protein ◽  
Adrenergic Receptor ◽  
Zona Glomerulosa ◽  
Type I ◽  
Adapter Proteins ◽  
Mrna Levels ◽  
Aldosterone Secretion ◽  
Signaling Crosstalk ◽  
Aldosterone Production ◽  
H295r Cells

Abstract Aldosterone is produced by adrenocortical zona glomerulosa (AZG) cells in response to hyperkalemia or angiotensin II (AngII) acting through its type I receptors (AT1Rs). AT1R is a G protein-coupled receptor (GPCR) that induces aldosterone synthesis and secretion via both G proteins and the GPCR adapter proteins βarrestins. AZG cells express all three subtypes of β-adrenergic receptor (AR) and respond to catecholamines by producing aldosterone. Being GPCRs, both activated βARs and AT1Rs are phosphorylated by GPCR-kinases (GRKs), followed by βarrestin binding to initiate G protein-independent signaling. Herein, we investigated whether the major adrenal GRKs, GRK2 and GRK5, are involved in catecholaminergic regulation of AngII-dependent aldosterone production. We used the human AZG cell line H295R, in which we measured aldosterone secretion via ELISA and synthesis via real-time PCR for steroidogenic acute regulatory (StAR) protein and CYP11B2 (aldosterone synthase) mRNA levels. Isoproterenol (Iso, a βAR full agonist) treatment significantly augmented AngII-dependent aldosterone synthesis (2.2+0.8-fold CYP11B2 & 1.6+0.5-fold StAR mRNA inductions over AngII alone; p<0.05, n=4), as well as secretion (2.3+0.8-fold of vehicle with Iso; 3.2+1.1-fold of vehicle with AngII; 7.4+1.1-fold of vehicle with Iso+AngII, p<0.05 vs. either agent alone; n=5) in H295R cells. Importantly, GRK2, but not the other major GRK isoform expressed in human adrenals GRK5, was indispensable for the catecholamine-mediated enhancement of aldosterone production in response to AngII in H295R cells. Specifically, GRK2 inhibition with the small molecule Cmpd101 abolished Iso effects on AngII-induced aldosterone synthesis and secretion (Iso+AngII-induced aldosterone secretion: 8.1+2.3-fold of vehicle without Cmpd101; 2.8+0.8-fold of vehicle with Cmpd101; p<0.05, n=5). In contrast, GRK5 knockout via CRISPR/Cas9 did not affect the synergism between isoproterenol and AngII in stimulating aldosterone production. Mechanistically, βAR-activated GRK2, but not GRK5, phosphorylated and activated the Ca2+-activated chloride channel anoctamine-1 (ANO1), also known as transmembrane member (TMEM)16A, ultimately increasing aldosterone production in H295R cells (Iso+10–6 M [Ca2+]-induced ANO1 activity of Cmpd101-pretreated cells: 55+15 % of non-Cmpd101-pretreated cells; p<0.05, n=5). AngII alone failed to stimulate GRK2 in H295R cells. In conclusion, GRK2 mediates a βAR-AT1R signaling crosstalk at the level of ANO1 activation, which results in enhanced aldosterone production in H295R cells. This finding suggests that adrenal GRK2 may be a molecular link connecting the sympathetic nervous and renin-angiotensin systems in the adrenal cortex and that GRK2 inhibition might be therapeutically advantageous for aldosterone suppression.

Mechanisms of ET-1 potentiation of angiotensin II stimulation of aldosterone production

1993 ◽  
Vol 265 (2) ◽  
pp. E179-E183 ◽  
Author(s):  
E. N. Cozza ◽  
C. E. Gomez-Sanchez
Keyword(s):  
Angiotensin Ii ◽  
Zona Glomerulosa ◽  
Ang Ii ◽  
Aldosterone Secretion ◽  
Direct Stimulation ◽  
Potentiation Effect ◽  
Aldosterone Production ◽  
Glomerulosa Cells ◽  
Pkc Inhibitors ◽  
Stimulation Of

Endothelin-1 (ET-1) exerts the following two types of aldosterone-stimulating actions on glomerulosa cells: ET-1-mediated direct stimulation of aldosterone secretion (per se effect) and potentiation of the aldosterone secretion to angiotensin II (ANG II; potentiation effect). The role of Ca2+ and protein kinase C (PKC) systems in these two effects was investigated. Incubations of calf cultured adrenal zona glomerulosa cells in low-Ca2+ media or in the presence of the Ca2+ channel antagonist verapamil reduced the aldosterone secretion to ET-1. When cells were preincubated with ET-1 in a low-Ca2+ media or in the presence of the Ca2+ channel antagonist verapamil, washed, and incubated in media with normal Ca2+, ANG II showed potentiation of ANG II-stimulated aldosterone secretion. The PKC inhibitors H-7 and staurosporine did not decrease ET-1-stimulated aldosterone secretion, but they inhibited the potentiation effect of ET-1 on ANG II-mediated aldosterone secretion. Adrenocorticotropic hormone desensitization or prolonged phorbol ester stimulation of PKC resulting in desensitization also resulted in the abolition of the ET-1-mediated ANG II potentiation of aldosterone secretion. The PKC inhibitors did not affect ANG II-stimulated aldosterone secretion. We conclude that ET-1 exerts a direct stimulation of aldosterone secretion through a mechanism dependent on Ca2+ and potentiates ANG II-mediated aldosterone stimulation through a mechanism involving PKC.

scholarly journals Targeted disruption of the Kcnj5 gene in the female mouse lowers aldosterone levels

2018 ◽  
Vol 132 (1) ◽  
pp. 145-156 ◽  
Author(s):  
Iris Hardege ◽  
Lu Long ◽  
Raya Al Maskari ◽  
Nicola Figg ◽  
Kevin M. O’Shaughnessy
Keyword(s):  
Zona Glomerulosa ◽  
K Channel ◽  
Peroxisome Proliferator ◽  
Aldosterone Secretion ◽  
Gene Encoding ◽  
Peroxisome Proliferator Activated Receptor ◽  
Adrenal Cells ◽  
Aldosterone Production ◽  
Inwardly Rectifying

Aldosterone is released from adrenal zona glomerulosa (ZG) cells and plays an important role in Na and K homoeostasis. Mutations in the human inwardly rectifying K channel CNJ type (KCNJ) 5 (KCNJ5) gene encoding the G-coupled inwardly rectifying K channel 4 (GIRK4) cause abnormal aldosterone secretion and hypertension. To better understand the role of wild-type (WT) GIRK4 in regulating aldosterone release, we have looked at aldosterone secretion in a Kcnj5 knockout (KO) mouse. We found that female but not male KO mice have reduced aldosterone levels compared with WT female controls, but higher levels of aldosterone after angiotensin II (Ang-II) stimulation. These differences could not be explained by sex differences in aldosterone synthase (Cyp11B2) gene expression in the mouse adrenal. Using RNAseq analysis to compare WT and KO adrenals, we showed that females also have a much larger set of differentially expressed adrenal genes than males (395 compared with 7). Ingenuity Pathway Analysis (IPA) of this gene set suggested that peroxisome proliferator activated receptor (PPAR) nuclear receptors regulated aldosterone production and altered signalling in the female KO mouse, which could explain the reduced aldosterone secretion. We tested this hypothesis in H295R adrenal cells and showed that the selective PPARα agonist fenofibrate can stimulate aldosterone production and induce Cyp11b2. Dosing mice in vivo produced similar results. Together our data show that Kcnj5 is important for baseline aldosterone secretion, but its importance is sex-limited at least in the mouse. It also highlights a novel regulatory pathway for aldosterone secretion through PPARα that may have translational potential in human hyperaldosteronism.

scholarly journals Steroidogenesis in Aldosterone-Producing Adenoma Revisited by Transcriptome Analysis

2005 ◽  
Vol 90 (12) ◽  
pp. 6638-6649 ◽  
Author(s):  
Guillaume Assié ◽  
Colette Auzan ◽  
Jean-Marie Gasc ◽  
Erno Baviera ◽  
André Balaton ◽  
...  
Keyword(s):  
Gene Expression ◽  
Angiotensin Ii ◽  
Calcium Binding ◽  
Density Lipoprotein ◽  
Zona Glomerulosa ◽  
Differentially Expressed ◽  
Calcium Activation ◽  
Starting Point ◽  
Aldosterone Production ◽  
Aldosterone Producing Adenoma

Context: Primary aldosteronism (PAL) is the most frequent cause of secondary arterial hypertension. In PAL, aldosterone production is chronic, excessive, and autonomous. Objective: The objective of this study was to identify the angiotensin-II independent alterations of steroidogenesis responsible for PAL. Design: Genomewide gene expression was compared in two tissues differentiated for aldosterone production, both nonstimulated by circulating angiotensin II and differing in their autonomy to produce aldosterone: aldosterone-producing adenoma (APA) and its adjacent dissected zona glomerulosa (ZG). Setting: The setting of this study was the Comete Network. Patients: Patients with APA were studied. Intervention: Transcriptome comparison was made of one APA and its adjacent ZG by serial analysis of gene expression; validation by in situ hybridization was performed for 19 genes in 11 samples. Outcome: The study outcome was genes differentially expressed in APA and adjacent ZG. Results: Activation of steroidogenesis in PAL is restricted to the overexpression of the enzymes producing aldosterone-specific steroids, aldosterone synthase and also 21-hydroxylase, suggesting that upstream precursor production is not limiting. Increased expression of high-density lipoprotein receptor, adrenodoxin and P450 oxidoreductase suggests that these systems provide cholesterol and electrons to the mitochondrial steroidogenic enzymes. As for acute stimulation of aldosterone production, an activation of calcium signaling is suggested by concordant overexpression of calcium-binding proteins or effectors. Calcium activation may result from an abnormal activity of Gq protein-coupled receptors. This calcium activation may be the starting point of the other gene expression changes observed in APA. Finally, other differentially expressed genes include three genes encoding unidentified proteins. Conclusion: This work provides an original and integrated view of the mechanisms of aldosterone production in PAL.

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.

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