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 Potassium Channel Mutant KCNJ5 T158A Expression in HAC-15 Cells Increases Aldosterone Synthesis

Endocrinology ◽  
2012 ◽  
Vol 153 (4) ◽  
pp. 1774-1782 ◽  
Author(s):  
Kenji Oki ◽  
Maria W. Plonczynski ◽  
Milay Luis Lam ◽  
Elise P. Gomez-Sanchez ◽  
Celso E. Gomez-Sanchez
Keyword(s):  
Potassium Channel ◽  
Primary Aldosteronism ◽  
Calcium Influx ◽  
Fold Increase ◽  
Transitional Zone ◽  
Selectivity Filter ◽  
Adrenal Cortical Carcinoma ◽  
Aldosterone Secretion ◽  
Familial Hyperaldosteronism ◽  
Type 3

Primary aldosteronism is the most common cause of secondary hypertension, most frequently due to an aldosterone-producing adenoma or idiopathic hyperaldosteronism. Somatic mutations of the potassium channel KCNJ5 in the region of the selectivity filter have been found in a significant number of aldosterone-producing adenomas. There are also familial forms of primary aldosteronism, one of which, familial hyperaldosteronism type 3 which to date has been found in one family who presented with a severe abnormality in aldosterone and 18-oxocortisol production and hypertrophy and hyperplasia of the transitional zone of the adrenal cortex. In familial hyperaldosteronism type 3, there is a genomic mutation causing a T158A change of amino acids within the selectivity filter region of the KCNJ5 gene. We are reporting our studies demonstrating that lentiviral-mediated expression of a gene carrying the T158A mutation of the KCNJ5 in the HAC15 adrenal cortical carcinoma cell line causes a 5.3-fold increase in aldosterone secretion in unstimulated HAC15-KCNJ5 cells and that forskolin-stimulated aldosterone secretion was greater than that of angiotensin II. Expression of the mutated KCNJ5 gene decreases plasma membrane polarization, allowing sodium and calcium influx into the cells. The calcium channel antagonist nifedipine and the calmodulin inhibitor W-7 variably inhibited the effect. Overexpression of the mutated KCNJ5 channel resulted in a modest decrease in HAC15 cell proliferation. These studies demonstrate that the T158A mutation of the KCNJ5 gene produces a marked stimulation in aldosterone biosynthesis that is dependent on membrane depolarization and sodium and calcium influx into the HAC15 adrenal cortical carcinoma cells.

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.

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.

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.

Abstract 277: Mutations in the KCNJ5 Gene Imply a Higher Lateralization Index at Adrenal Vein Sampling for Primary Aldosteronism

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Teresa M Seccia ◽  
Franco Mantero ◽  
Claudio Letizia ◽  
Maniselvan Kuppusamy ◽  
Marlena Barisa ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Somatic Mutations ◽  
Contralateral Side ◽  
Adrenal Vein ◽  
K Channel ◽  
Coding Region ◽  
Aldosterone Secretion ◽  
Adrenal Vein Sampling ◽  
Lateralization Index

Background. The mutations that affect the selectivity filter of the KCNJ5 K+ channel can play a role in triggering and/or maintaining aldosterone oversecretion in primary aldosteronism (PA). We therefore hypothesized that these somatic mutations can be associated with an increased aldosterone secretion from the APA, thus translating in raised plasma aldosterone concentrations (PAC) in the ipsilateral adrenal vein. Aim. To investigate if the lateralization index (LI) at adrenal vein sampling (AVS) is higher in the patients with an APA carrying the mutation (KCNJ5mut), as compared to those without the mutation (KCNJ5wt). Methods. Ninety-two consecutive PA patients who underwent AVS and received diagnosis of APA based on the four corners criteria were recruited. Unequivocal information on the presence or absence of the KCNJ5 mutations was available for each patient. The selectivity index (SI) was calculated as ratio between the right or left adrenal vein PCC (PCCside) and the infrarenal IVC PCC and a cutoff of 2.00 was used. The lateralization index (LI) was calculated in the bilaterally selective AVS as the ratio of PAC/PCC at the APA side to PAC/PCC at the contralateral side. We sequenced the KCNJ5 coding region spanning aminoacids 122 to 199, which include the selectivity filer. Results. The overall prevalence rate of KCNJ5 somatic mutations was 34%; G151R, L168R and T158A mutations were found in 19, 10 and 1 APA respectively. The G151E mutation was not found. The KCNJ5mut and KCNJ5wt groups were similar for gender, age, sK+ levels, while PAC and ARR were higher, and PRA lower (all p<0.05) in the KCNJ5 mut group. In the latter group the LI was higher than in the KCNJ5wt group (29.3± 6.7 vs 16.7±3.9, p< 0.02). This was due to a PAC/PCC ratio which was higher in the adrenal vein ipsilateral to the APA side and lower contralaterally in the KCNJ5mut group. Conclusions. These results provide direct in vivo evidence for a higher aldosterone secretion from APA carrying the KCNJ5 mutations, which translates into higher values of the LI, compared to the tumors without such mutations. Hence, the presence of these KCNJ5 mutations can affect the accuracy of the AVS-based diagnosis of the subtype of PA.

Human Adrenal Glomerulosa Cells Express K2P and GIRK Potassium Channels that are inhibited by AngII and ACTH

2021 ◽  
Author(s):  
John J. Enyeart ◽  
Judith A. Enyeart
Keyword(s):  
G Protein ◽  
Zona Glomerulosa ◽  
Time Dependent ◽  
Aldosterone Secretion ◽  
Girk Channels ◽  
Whole Cell ◽  
Whole Cell Patch Clamp ◽  
Girk Channel ◽  
Inwardly Rectifying ◽  
G Protein Coupled

In whole-cell patch clamp recordings, it was discovered that normal human adrenal zona glomerulosa (AZG) cells express members of the three major families of K+ channels. Among these are a two pore (K2P) leak-type and a G-protein-coupled, inwardly-rectifying (GIRK) channel, both inhibited by peptide hormones that stimulate aldosterone secretion. The K2P current displayed properties identifying it as TREK-1 (KCNK2). This outwardly-rectifying current was activated by arachidonic acid and inhibited by angiotensin II (AngII), adrenocorticotrophic hormone (ACTH), and forskolin. The activation and inhibition of TREK-1 was coupled to AZG cell hyperpolarization and depolarization, respectively. A second K2P channel, TASK-1 (KCNK3), was expressed at a lower density in AZG cells. Human AZG cells also express inwardly rectifying K+ current(s) (KIR) that include quasi-instantaneous and time-dependent components. This is the first report demonstrating the presence of KIR in whole cell recordings from AZG cells of any species. The time-dependent current was selectively inhibited by AngII, and ACTH, identifying it as a G protein-coupled (GIRK) channel, most likely KIR3.4 (KCNJ5). The quasi-instantaneous KIR current was not inhibited by AngII or ACTH, and may be a separate non-GIRK current. Finally, AZG cells express a voltage-gated, rapidly inactivating K+ current whose properties identified as KV1.4 (KCNA4), a conclusion confirmed by Northern blot. These findings demonstrate that human AZG cells express K2P and GIRK channels whose inhibition by AngII and ACTH are likely coupled to depolarization-dependent secretion. They further demonstrate that human AZG K+ channels differ fundamentally from the widely adopted rodent models for human aldosterone secretion.

scholarly journals PROGRESS IN ALDOSTERONISM: A review of the prevalence of primary aldosteronism in pre-hypertension and hypertension

2015 ◽  
Vol 172 (5) ◽  
pp. R191-R203 ◽  
Author(s):  
George Piaditis ◽  
Athina Markou ◽  
Labrini Papanastasiou ◽  
Ioannis I Androulakis ◽  
Gregory Kaltsas
Keyword(s):  
Primary Aldosteronism ◽  
Clinical Phenotype ◽  
Ion Homeostasis ◽  
Genetic Alterations ◽  
Zona Glomerulosa ◽  
Receptor Expression ◽  
Aldosterone Secretion ◽  
Disease Heterogeneity ◽  
Aldosterone Antagonists ◽  
Cardiovascular Morbidity And Mortality

Primary aldosteronism (PA) secondary to excessive and/or autonomous aldosterone secretion from the renin–angiotensin system accounts for ∼10% of cases of hypertension and is primarily caused by bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenomas (APAs). Although the diagnosis has traditionally been supported by low serum potassium levels, normokalaemic and even normotensive forms of PA have been identified expanding further the clinical phenotype. Moreover, recent evidence has shown that serum aldosterone correlates with increased blood pressure (BP) in the general population and even moderately raised aldosterone levels are linked to increased cardiovascular morbidity and mortality. In addition, aldosterone antagonists are effective in BP control even in patients without evidence of dysregulated aldosterone secretion. These findings indicate a higher prevalence of aldosterone excess among hypertensive patients than previously considered that could be attributed to disease heterogeneity, aldosterone level fluctuations related to an ACTH effect or inadequate sensitivity of current diagnostic means to identify apparent aldosterone excess. In addition, functioning aberrant receptors expressed in the adrenal tissue have been found in a subset of PA cases that could also be related to its pathogenesis. Recently a number of specific genetic alterations, mainly involving ion homeostasis across the membrane of zona glomerulosa, have been detected in ∼50% of patients with APAs. Although specific genotype/phenotype correlations have not been clearly identified, differential expression of these genetic alterations could also account for the wide clinical phenotype, variations in disease prevalence and performance of diagnostic tests. In the present review, we critically analyse the current means used to diagnose PA along with the role that ACTH, aberrant receptor expression and genetic alterations may exert, and provide evidence for an increased prevalence of aldosterone dysregulation in patients with essential hypertension and pre-hypertension.

scholarly journals Palmitoylation regulates plasma membrane–nuclear shuttling of R7BP, a novel membrane anchor for the RGS7 family

2005 ◽  
Vol 169 (4) ◽  
pp. 623-633 ◽  
Author(s):  
Ryan M. Drenan ◽  
Craig A. Doupnik ◽  
Maureen P. Boyle ◽  
Louis J. Muglia ◽  
James E. Huettner ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Potassium Channel ◽  
G Protein ◽  
Rgs Proteins ◽  
Membrane Anchor ◽  
Channel Activation ◽  
Gpcr Signaling ◽  
Inward Rectifying Potassium Channel ◽  
Nuclear Shuttling ◽  
G Protein Coupled

The RGS7 (R7) family of RGS proteins bound to the divergent Gβ subunit Gβ5 is a crucial regulator of G protein–coupled receptor (GPCR) signaling in the visual and nervous systems. Here, we identify R7BP, a novel neuronally expressed protein that binds R7–Gβ5 complexes and shuttles them between the plasma membrane and nucleus. Regional expression of R7BP, Gβ5, and R7 isoforms in brain is highly coincident. R7BP is palmitoylated near its COOH terminus, which targets the protein to the plasma membrane. Depalmitoylation of R7BP translocates R7BP–R7–Gβ5 complexes from the plasma membrane to the nucleus. Compared with nonpalmitoylated R7BP, palmitoylated R7BP greatly augments the ability of RGS7 to attenuate GPCR-mediated G protein–regulated inward rectifying potassium channel activation. Thus, by controlling plasma membrane nuclear–shuttling of R7BP–R7–Gβ5 complexes, reversible palmitoylation of R7BP provides a novel mechanism that regulates GPCR signaling and potentially transduces signals directly from the plasma membrane to the nucleus.

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.

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