K+ Channel Mutations in Adrenal Aldosterone-Producing Adenomas and Hereditary Hypertension

Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
Science (Impact Factor: 33.61). 02/2011; 331(6018):768-72. DOI: 10.1126/science.1198785
Source: PubMed


Endocrine tumors such as aldosterone-producing adrenal adenomas (APAs), a cause of severe hypertension, feature constitutive
hormone production and unrestrained cell proliferation; the mechanisms linking these events are unknown. We identify two recurrent
somatic mutations in and near the selectivity filter of the potassium (K+) channel KCNJ5 that are present in 8 of 22 human APAs studied. Both produce increased sodium (Na+) conductance and cell depolarization, which in adrenal glomerulosa cells produces calcium (Ca2+) entry, the signal for aldosterone production and cell proliferation. Similarly, we identify an inherited KCNJ5 mutation that produces increased Na+ conductance in a Mendelian form of severe aldosteronism and massive bilateral adrenal hyperplasia. These findings explain
pathogenesis in a subset of patients with severe hypertension and implicate loss of K+ channel selectivity in constitutive cell proliferation and hormone production.

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    • "When EAST syndrome mutant channels were expressed in our system, the reversal potentials were less negative (Figures 5A and S4C), and the pNCC abundance was lower (Figure 5B and Table S4) than when wild-type channels were expressed. Mutations in the selectivity filter of a related potassium channel in adrenal cells were shown to cause hyperaldosteronism by increasing the channel Na + /K + permeability ratio (Choi et al., 2011). As another test of the role of membrane voltage on pNCC, we mutated the homologous amino acid residue in Kir4.1 (G130). "
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    ABSTRACT: Dietary potassium deficiency, common in modern diets, raises blood pressure and enhances salt sensitivity. Potassium homeostasis requires a molecular switch in the distal convoluted tubule (DCT), which fails in familial hyperkalemic hypertension (pseudohypoaldosteronism type 2), activating the thiazide-sensitive NaCl cotransporter, NCC. Here, we show that dietary potassium deficiency activates NCC, even in the setting of high salt intake, thereby causing sodium retention and a rise in blood pressure. The effect is dependent on plasma potassium, which modulates DCT cell membrane voltage and, in turn, intracellular chloride. Low intracellular chloride stimulates WNK kinases to activate NCC, limiting potassium losses, even at the expense of increased blood pressure. These data show that DCT cells, like adrenal cells, sense potassium via membrane voltage. In the DCT, hyperpolarization activates NCC via WNK kinases, whereas in the adrenal gland, it inhibits aldosterone secretion. These effects work in concert to maintain potassium homeostasis. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell Metabolism 01/2015; 21(1):39-50. DOI:10.1016/j.cmet.2014.12.006 · 17.57 Impact Factor
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    • "We will focus this review on the mechanism and structural details of polyamine block of the Kir2 subfamily channels (which are particularly sensitive to polyamines), as well as some of the details of their physiological roles and disruption in genetic channelopathies. It is noteworthy that “weak” inward rectifiers (with shallow voltage dependence, and weak polyamine sensitivity) play many important physiological roles, impacting diverse processes such as hormone secretion (Koster et al., 2000; Choi et al., 2011), ion transport in the nephron (Simon et al., 1996), and control of ionic gradients in the inner ear (Scholl et al., 2009). Thus, we also refer readers to a recent broad review that provides an overview of the structure, function, and physiology of the entire Kir channel family as an excellent starting point for further discussion of other Kir channel types (Hibino et al., 2010). "
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    Frontiers in Physiology 08/2014; 5:325. DOI:10.3389/fphys.2014.00325 · 3.53 Impact Factor
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    • "DNA sequencing and mutations in KCNJ5 APA cases (n = 74) were submitted to PCR using a KCNJ5 primer (forward 5 0 -CGA CCA AGA GTG GAT TCC TT- 0 3, reverse 5 0 -AGG GTC TCC GCT CTC TTC TT- 0 3) as described by our group [11]. Analysis of the purified DNA was carried out with a Abi Prism 310 genetic analyser (Applied Biosystems, Foster City, CA, USA), and mutations at the G151R and L168R regions of the KCNJ5 gene were analyzed as described [4] "
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