Both TASK-3 and TREK-1 two-pore loop K channels are expressed in H295R cells and modulate their membrane potential and aldosterone secretion

Brenner, Tanja; O’Shaughnessy, Kevin M.

doi:10.1152/ajpendo.90652.2008

Cited by 31 publications

(22 citation statements)

References 30 publications

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Section: Expression In H295r Cellsmentioning

confidence: 99%

“…18 The wild-type (WT) human channel (containing the common variant of rs7102584, ie, E282) was sourced in the pCMV-AC-GFP expression vector from Origene (Rockville, MD http://www.origene.com) and site-mutated as described previously. 18 All plasmid sequences were confirmed by Sanger sequencing on a Beckman CEQ8000 platform. The plasmid constructs were transiently expressed in H295R cells by electroporation using the Nucleofector device and reagents from the Nucleofector kit R according to manufacturer instructions (http:// www.Lonza.com).…”

Section: Expression In H295r Cellsmentioning

confidence: 99%

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Role for Germline Mutations and a Rare Coding Single Nucleotide Polymorphism Within the KCNJ5 Potassium Channel in a Large Cohort of Sporadic Cases of Primary Aldosteronism

Murthy

Massimo

et al. 2014

Hypertension

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P rimary hyperaldosteronism (PA) is now recognized as a common, treatable, and potentially curable form of hypertension. In fact it may account for ≥10% of cases of what would previously have been labeled as essential hypertension.1,2 The excessive aldosterone production usually derives from either an aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia. The balance between these 2 pathologies varies; however, in most recently published series, bilateral adrenal hyperplasia is about twice as common as APA. 3,4 Although the majority of PA is sporadic, there are monogenic familial forms of the condition (familial hyperaldosteronism types I, II, and III [FH-I, FH-II, and FH-III]). The molecular basis for FHI, glucocorticoid-remediable aldosteronism, has been well understood for >2 decades and involves a recombination event that places the aldosterone synthase enzyme, CYP11B2, under the control of ACTH. 5,6 In contrast, the molecular genetics for FHIII has been resolved recently with the discovery that they are caused by germline mutations that cluster in the selectivity filter of a potassium channel, KCNJ5. 7-9 These mutations affect the Na + permeability of the channel, which is thought to lead to depolarization of zona glomerulosa cells in the adrenal cortex thereby activating aldosterone release.Before the discovery of selectivity filter mutations in KCNJ5, this potassium channel was not even recognized as being expressed in the human adrenal gland. However, it is now known to be important in sporadic as well as the much rarer syndromic forms of PA, 10 with ≤40% of APAs carrying somatic mutations in the same KCNJ5 gene. 7,11 The coding sequence for KCNJ5 has been resequenced in a large collection of adrenal lesions (both APAs and non-APAs) without identifying further somatic mutations outside of the selectivity filter itself. 12However, we hypothesized that rare variants, in the form of See Editorial Commentary, pp 668-669Abstract-Primary aldosteronism (autonomous aldosterone production with suppressed renin) plays an important pathophysiological role in what has been previously labeled as essential hypertension. Besides the recently described germline mutations in the KCNJ5 potassium channel associated with familial primary aldosteronism, somatic mutations in the same channel have been identified within aldosterone-producing adenomas. In this study, we have resequenced the flanking and coding region of KCNJ5 in peripheral blood DNA from 251 white subjects with primary aldosteronism to look for rare variants that might be important for the pathophysiology of sporadic primary aldosteronism. We have identified 3 heterozygous missense mutations (R52H, E246K, and G247R) in the cohort and found that 12 (5% of the cohort) were carriers for the rare nonsynonymous single nucleotide polymorphism rs7102584 causing E282Q substitution of KCNJ5. By expressing the channels in Xenopus oocytes and human adrenal H295R cells, we have shown that the R52H, E246K, and E282Q substitutions are functional, but the G247R...

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Section: Expression In H295r Cellsmentioning

confidence: 99%

Section: Expression In H295r Cellsmentioning

confidence: 99%

Role for Germline Mutations and a Rare Coding Single Nucleotide Polymorphism Within the KCNJ5 Potassium Channel in a Large Cohort of Sporadic Cases of Primary Aldosteronism

Murthy

Massimo

et al. 2014

Hypertension

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“…This response is carried out through both the mineralocorticoid hormone aldosterone and aldosterone-independent mechanisms [42]. Expression of the inward-rectifying pore channels in the glomerulosa cells of adrenal glands, TWIK and, more specifically, TASK, maintains the membrane potential close to the equilibrium potential for K + , thus making the glomerulosa cells sensitive to changes in plasma K + [43,44,45]. Therefore, changes in plasma K + will depolarize the glomerulosa cells, favoring Ca 2+ entry which will stimulate aldosterone synthesis [43,44].…”

Section: Regulation Of Renal K+ Excretion: High-k+ Versus Low-k+ Dietmentioning

confidence: 99%

“…Expression of the inward-rectifying pore channels in the glomerulosa cells of adrenal glands, TWIK and, more specifically, TASK, maintains the membrane potential close to the equilibrium potential for K + , thus making the glomerulosa cells sensitive to changes in plasma K + [43,44,45]. Therefore, changes in plasma K + will depolarize the glomerulosa cells, favoring Ca 2+ entry which will stimulate aldosterone synthesis [43,44]. The increased levels of aldosterone will in turn stimulate the mineralocorticoid receptor in the aldosterone-sensitive distal nephron (ASDN) favoring K + secretion.…”

Section: Regulation Of Renal K+ Excretion: High-k+ Versus Low-k+ Dietmentioning

confidence: 99%

Independent Regulation of Na+ and K+ Balance by the Kidney

Castañeda‐Bueno

Arroyo

Gamba³

2011

Med Princ Pract

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The understanding of the independent regulation of sodium and potassium by the kidney has remained elusive. Recent evidence now points to dissimilar regulatory mechanisms in ion handling, dependent on the presence of either aldosterone alone or angiotensin II with aldosterone among other factors. This review summarizes past and present information in an attempt to reconcile the current concepts of differential regulation of sodium and potassium balance through the with-no-lysine (K) kinase (WNK) system and the previous knowledge regarding ion transport mechanisms in the distal nephron.

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“…AT 1 receptors in these adrenocortical cells have been linked to the activation of multiple signaling pathways (28,29,45,50). However, the Gq-dependent activation of PLC␤, leading to the hydrolysis of membrane-associated phosphatidylinositol 4,5-bisphosphate (PIP 2 ) and the production of inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol (DAG), is the principal signaling mechanism initiating ANG II responses (46).…”

mentioning

confidence: 99%

Calcium-dependent inhibition of adrenal TREK-1 channels by angiotensin II and ionomycin

Enyeart

Liu

Enyeart

2011

American Journal of Physiology-Cell Physiology

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Bovine adrenocortical cells express bTREK-1 K ϩ (bovine KCNK2) channels that are inhibited by ANG II through a Gq-coupled receptor by separate Ca 2ϩ and ATP hydrolysis-dependent signaling pathways. Whole cell and single patch clamp recording from adrenal zona fasciculata (AZF) cells were used to characterize Ca 2ϩ -dependent inhibition of bTREK-1. In whole cell recordings with pipette solutions containing 0.5 mM EGTA and no ATP, the Ca 2ϩ ionophore ionomycin (1 M) produced a transient inhibition of bTREK-1 that reversed spontaneously within minutes. At higher concentrations, ionomycin (5-10 M) produced a sustained inhibition of bTREK-1 that was reversible upon washing, even in the absence of hydrolyzable [ATP] i. BAPTA was much more effective than EGTA at suppressing bTREK-1 inhibition by ANG II. When intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i) was buffered to 20 nM with either 11 mM BAPTA or EGTA, ANG II (10 nM) inhibited bTREK-1 by 12.0 Ϯ 4.5% (n ϭ 11) and 59.3 Ϯ 8.4% (n ϭ 4), respectively. Inclusion of the water-soluble phosphatidylinositol 4,5-bisphosphate (PIP 2) analog DiC8PI(4,5)P2 in the pipette failed to increase bTREK-1 expression or reduce its inhibition by ANG II. The open probability (P o) of unitary bTREK-1 channels recorded from inside-out patches was reduced by Ca 2ϩ (10 -35 M) in a concentration-dependent manner. These results are consistent with a model in which ANG II inhibits bTREK-1 K ϩ channels by a Ca 2ϩ -dependent mechanism that does not require the depletion of membrane-associated PIP 2. They further indicate that the Ca 2ϩ source is located in close proximity within a "Ca 2ϩ nanodomain" of bTREK-1 channels, where [Ca 2ϩ ]i may reach concentrations of Ͼ10 M. bTREK-1 is the first two-pore K ϩ channel shown to be inhibited by Ca 2ϩ through activation of a G protein-coupled receptor. adrenocortical; potassium channel; ionomycin; phosphatidylinositol 4,5-bisphosphate; nanodomain BOVINE ADRENOCORTICAL CELLS including cortisol-secreting zona fasciculata (AZF) cells and aldosterone-secreting zona glomerulosa (AZG) cells express bTREK-1 (bovine KCNK2) leak-type K ϩ channels that function pivotally in the physiology of corticosteroid hormone secretion (14,17,18,35). These two-pore, four-transmembrane spanning (2P/4TMS) K ϩ channels set the resting membrane potential of bovine adrenocortical cells and are inhibited by ANG II at concentrations identical to those that trigger membrane depolarization and corticosteroid secretion (14,35).The signaling pathways that couple ANG II receptors to bTREK-1 inhibition are complex and only partially understood. In both AZF and AZG cells, ANG II inhibits bTREK-1 through activation of a Gq-coupled AT 1 receptor (14,35,36). AT 1 receptors in these adrenocortical cells have been linked to the activation of multiple signaling pathways (28,29,45,50). However, the Gq-dependent activation of PLC␤, leading to the hydrolysis of membrane-associated phosphatidylinositol 4,5-bisphosphate (PIP 2 ) and the production of inositol 1,4,5-trisphosphate (IP 3 ) and diacylglyc...

show abstract

Both TASK-3 and TREK-1 two-pore loop K channels are expressed in H295R cells and modulate their membrane potential and aldosterone secretion

Cited by 31 publications

References 30 publications

Role for Germline Mutations and a Rare Coding Single Nucleotide Polymorphism Within the KCNJ5 Potassium Channel in a Large Cohort of Sporadic Cases of Primary Aldosteronism

Role for Germline Mutations and a Rare Coding Single Nucleotide Polymorphism Within the KCNJ5 Potassium Channel in a Large Cohort of Sporadic Cases of Primary Aldosteronism

Independent Regulation of Na+ and K+ Balance by the Kidney

Calcium-dependent inhibition of adrenal TREK-1 channels by angiotensin II and ionomycin

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