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Na/K Pump Mutations Associated with Primary Hyperaldosteronism Cause Loss of Function.
Meyer DJ, Gatto C, Artigas P.
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Primary hyperaldosteronism (Conn's syndrome), a common cause of secondary hypertension, is frequently produced by unilateral aldosterone-producing adenomas that carry mutations in ion-transporting genes, including ATP1A1, encoding the Na/K pump's α1 subunit. Whether Na/K pump mutant-mediated inward currents are required to depolarize the cell and increase aldosterone production remains unclear, as such currents were observed in four out of five mutants described so far. Here, we use electrophysiology and uptake of the K+ congener 86Rb+, to characterize the effects of eight additional Na/K pump mutations in transmembrane segments TM1 (delM102-L103, delL103-L104, and delM102-I106), TM4 (delI322-I325 and I327S), and TM9 (delF956-E961, delF959-E961, and delE960-L964), expressed in Xenopus oocytes. All deletion mutants induced abnormal inward currents of different amplitudes at physiological voltages, while I327S lacked such currents. A detailed functional characterization revealed that I327S significantly reduces intracellular Na+ affinity without altering affinity for external K+. 86Rb+-uptake experiments show that I327S dramatically impairs function under physiological concentrations of Na+ and K+. Since Na/K pumps in the adrenal cortex may be formed by association of α1 with β3 instead of β1 subunits, we evaluated whether G99R (another mutant without inward currents when associated with β1) would show inward currents when associated with β3. We found that the kinetic characteristics of either mutant or wild-type α1β3 pumps expressed in Xenopus oocytes to be indistinguishable from those of α1β1 pumps. The observed functional consequences of each hyperaldosteronism mutant point to the loss of Na/K pump function as the common feature of all mutants, which is sufficient to induce hyperaldosteronism.
Abe,
Crystal structures of the gastric proton pump.
2018, Pubmed
Abe,
Crystal structures of the gastric proton pump.
2018,
Pubmed Åkerström,
Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas.
2015,
Pubmed Artigas,
Ouabain affinity determining residues lie close to the Na/K pump ion pathway.
2006,
Pubmed
,
Xenbase Azizan,
Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension.
2013,
Pubmed Beuschlein,
Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension.
2013,
Pubmed Blanco,
Na,K-ATPase subunit heterogeneity as a mechanism for tissue-specific ion regulation.
2005,
Pubmed Choi,
K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.
2011,
Pubmed Cornelius,
Uncoupled Na+-efflux on reconstituted shark Na,K-ATPase is electrogenic.
1989,
Pubmed Crambert,
Transport and pharmacological properties of nine different human Na, K-ATPase isozymes.
2000,
Pubmed
,
Xenbase Crambert,
Phospholemman (FXYD1) associates with Na,K-ATPase and regulates its transport properties.
2002,
Pubmed
,
Xenbase Daniil,
CACNA1H Mutations Are Associated With Different Forms of Primary Aldosteronism.
2016,
Pubmed Fernandes-Rosa,
A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism.
2018,
Pubmed Friedrich,
ATP1A2 Mutations in Migraine: Seeing through the Facets of an Ion Pump onto the Neurobiology of Disease.
2016,
Pubmed Grădinaru,
Probing the extracellular access channel of the Na,K-ATPase.
2015,
Pubmed Guagliardo,
Minireview: aldosterone biosynthesis: electrically gated for our protection.
2012,
Pubmed Habeck,
Stimulation, inhibition, or stabilization of Na,K-ATPase caused by specific lipid interactions at distinct sites.
2015,
Pubmed Hajnóczky,
Angiotensin-II inhibits Na+/K+ pump in rat adrenal glomerulosa cells: possible contribution to stimulation of aldosterone production.
1992,
Pubmed Hermans,
The antagonistic effect of K+o and dihydro-ouabain on the Na+ pump current of single rat and guinea-pig cardiac cells.
1995,
Pubmed Hilbers,
Tuning of the Na,K-ATPase by the beta subunit.
2016,
Pubmed
,
Xenbase Holmgren,
Charge translocation by the Na+/K+ pump under Na+/Na+ exchange conditions: intracellular Na+ dependence.
2006,
Pubmed
,
Xenbase Hu,
Zona glomerulosa cells of the mouse adrenal cortex are intrinsic electrical oscillators.
2012,
Pubmed Hunyady,
Na+-H+ and Na+-Ca2+ exchange in glomerulosa cells: possible role in control of aldosterone production.
1988,
Pubmed Isaksen,
Hypothermia-induced dystonia and abnormal cerebellar activity in a mouse model with a single disease-mutation in the sodium-potassium pump.
2017,
Pubmed
,
Xenbase Jaisser,
Modulation of the Na,K-pump function by beta subunit isoforms.
1994,
Pubmed
,
Xenbase Kanai,
Crystal structure of a Na+-bound Na+,K+-ATPase preceding the E1P state.
2013,
Pubmed Kopec,
Molecular mechanism of Na(+),K(+)-ATPase malfunction in mutations characteristic of adrenal hypertension.
2014,
Pubmed Lassuthova,
Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2.
2018,
Pubmed
,
Xenbase Laursen,
Crystal structure of the high-affinity Na+K+-ATPase-ouabain complex with Mg2+ bound in the cation binding site.
2013,
Pubmed Liu,
Susceptibility of β1 Na+-K+ pump subunit to glutathionylation and oxidative inhibition depends on conformational state of pump.
2012,
Pubmed Matthews,
Ionic dependence of adrenal steroidogenesis and ACTH-induced changes in the membrane potential of adrenocortical cells.
1973,
Pubmed Meier,
Hyperpolarization-activated inward leakage currents caused by deletion or mutation of carboxy-terminal tyrosines of the Na+/K+-ATPase {alpha} subunit.
2010,
Pubmed
,
Xenbase Meyer,
On the effect of hyperaldosteronism-inducing mutations in Na/K pumps.
2017,
Pubmed
,
Xenbase Mitchell,
Sodium and proton effects on inward proton transport through Na/K pumps.
2014,
Pubmed
,
Xenbase Monticone,
a Novel Y152C KCNJ5 mutation responsible for familial hyperaldosteronism type III.
2013,
Pubmed Moseley,
Genetic profiling reveals global changes in multiple biological pathways in the hearts of Na, K-ATPase alpha 1 isoform haploinsufficient mice.
2005,
Pubmed Mulatero,
Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents.
2004,
Pubmed Nakao,
Voltage dependence of Na translocation by the Na/K pump.
,
Pubmed Natke,
Electrical responses in cat adrenal cortex: possible relation to aldosterone secretion.
1979,
Pubmed Nishimoto,
Case Report: Nodule Development From Subcapsular Aldosterone-Producing Cell Clusters Causes Hyperaldosteronism.
2016,
Pubmed Ogawa,
Sequential substitution of K(+) bound to Na(+),K(+)-ATPase visualized by X-ray crystallography.
2015,
Pubmed Ogawa,
Crystal structure of the sodium-potassium pump (Na+,K+-ATPase) with bound potassium and ouabain.
2009,
Pubmed Peluffo,
Quaternary organic amines inhibit Na,K pump current in a voltage-dependent manner: direct evidence of an extracellular access channel in the Na,K-ATPase.
2004,
Pubmed Ratheal,
Selectivity of externally facing ion-binding sites in the Na/K pump to alkali metals and organic cations.
2010,
Pubmed
,
Xenbase Rossi,
A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients.
2006,
Pubmed Sakai,
Sodium--potassium pump current in rabbit sino-atrial node cells.
1996,
Pubmed Sampedro Castañeda,
A novel ATP1A2 mutation in a patient with hypokalaemic periodic paralysis and CNS symptoms.
2018,
Pubmed
,
Xenbase Schlingmann,
Germline De Novo Mutations in ATP1A1 Cause Renal Hypomagnesemia, Refractory Seizures, and Intellectual Disability.
2018,
Pubmed Schneeberger,
Ion selectivity of the cytoplasmic binding sites of the Na,K-ATPase: II. Competition of various cations.
2001,
Pubmed Scholl,
Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5.
2012,
Pubmed Scholl,
Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism.
2015,
Pubmed Scholl,
CLCN2 chloride channel mutations in familial hyperaldosteronism type II.
2018,
Pubmed Seccia,
The Biology of Normal Zona Glomerulosa and Aldosterone-Producing Adenoma: Pathological Implications.
2018,
Pubmed Shinoda,
Crystal structure of the sodium-potassium pump at 2.4 A resolution.
2009,
Pubmed Spät,
Control of aldosterone secretion: a model for convergence in cellular signaling pathways.
2004,
Pubmed Spät,
Glomerulosa cell--a unique sensor of extracellular K+ concentration.
2004,
Pubmed Stanley,
Importance of the Voltage Dependence of Cardiac Na/K ATPase Isozymes.
2015,
Pubmed
,
Xenbase Stanley,
External Ion Access in the Na/K Pump: Kinetics of Na+, K+, and Quaternary Amine Interaction.
2018,
Pubmed
,
Xenbase Stanley,
Intracellular Requirements for Passive Proton Transport through the Na+,K+-ATPase.
2016,
Pubmed
,
Xenbase Vedovato,
Route, mechanism, and implications of proton import during Na+/K+ exchange by native Na+/K+-ATPase pumps.
2014,
Pubmed
,
Xenbase Wang,
A conformation of Na(+)-K+ pump is permeable to proton.
1995,
Pubmed
,
Xenbase Williams,
Somatic ATP1A1, ATP2B3, and KCNJ5 mutations in aldosterone-producing adenomas.
2014,
Pubmed Yingst,
Insights into the mechanism by which inhibition of Na,K-ATPase stimulates aldosterone production.
1999,
Pubmed Yu,
Enzymatic properties of human Na,K-ATPase alpha1beta3 isozyme.
1997,
Pubmed Zheng,
A novel somatic mutation 145-147delETEinsK in KCNJ5 increases aldosterone production.
2017,
Pubmed
