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1.
Identification of the Large-Conductance Ca2+-Regulated Potassium Channel in Mitochondria of Human Bronchial Epithelial Cells.
Sek, A, Kampa, RP, Kulawiak, B, Szewczyk, A, Bednarczyk, P
Molecules (Basel, Switzerland). 2021;(11)
Abstract
Mitochondria play a key role in energy metabolism within the cell. Potassium channels such as ATP-sensitive, voltage-gated or large-conductance Ca2+-regulated channels have been described in the inner mitochondrial membrane. Several hypotheses have been proposed to describe the important roles of mitochondrial potassium channels in cell survival and death pathways. In the current study, we identified two populations of mitochondrial large-conductance Ca2+-regulated potassium (mitoBKCa) channels in human bronchial epithelial (HBE) cells. The biophysical properties of the channels were characterized using the patch-clamp technique. We observed the activity of the channel with a mean conductance close to 285 pS in symmetric 150/150 mM KCl solution. Channel activity was increased upon application of the potassium channel opener NS11021 in the micromolar concentration range. The channel activity was completely inhibited by 1 µM paxilline and 300 nM iberiotoxin, selective inhibitors of the BKCa channels. Based on calcium and iberiotoxin modulation, we suggest that the C-terminus of the protein is localized to the mitochondrial matrix. Additionally, using RT-PCR, we confirmed the presence of α pore-forming (Slo1) and auxiliary β3-β4 subunits of BKCa channel in HBE cells. Western blot analysis of cellular fractions confirmed the mitochondrial localization of α pore-forming and predominately β3 subunits. Additionally, the regulation of oxygen consumption and membrane potential of human bronchial epithelial mitochondria in the presence of the potassium channel opener NS11021 and inhibitor paxilline were also studied. In summary, for the first time, the electrophysiological and functional properties of the mitoBKCa channel in a bronchial epithelial cell line were described.
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2.
Oral sodium bicarbonate in people on haemodialysis: a randomised controlled trial.
Kourtellidou, SI, Ashby, DR, Johansson, LR
BMC nephrology. 2021;(1):346
Abstract
BACKGROUND Adverse events and mortality tend to cluster around dialysis sessions, potentially due to the impact of the saw-toothed profile of uraemic toxins such as potassium, peaking pre-dialysis and rapidly dropping during dialysis. Acidosis could be contributing to this harm by exacerbating a rise in potassium. The objectives of this study were to investigate the effects of oral bicarbonate treatment on reducing inter-dialytic potassium gain as well as other clinical consequences of preserving muscle mass and function and reducing intradialytic arrhythmia risk in people on haemodialysis. METHODS Open-label randomised controlled trial in a single-centre (London, UK). Forty-three clinically stable adults on haemodialysis were recruited, with a 6 month average pre-dialysis serum bicarbonate level < 22 mmol/l and potassium > 4 mmol/l. Thirty-three participants completed the study. Oral sodium bicarbonate tablets titrated up to a maximum of 3 g bd (6 g total) in intervention group for 12 weeks versus no treatment in the control group. Outcomes compared intervention versus non-intervention phases in the treated group and equivalent time points in the control group: pre- and post-dialysis serum potassium; nutritional assessments: muscle mass and handgrip strength and electrocardiograms (ECGs) pre and post dialysis. RESULTS Participants took an average of 3.7 ± 0.5 g sodium bicarbonate a day. In the intervention group, inter-dialytic potassium gain was reduced from 1.90 ± 0.60 to 1.69 ± 0.49 mmol/l (p = 0.032) and pre-dialysis potassium was reduced from 4.96 ± 0.62 to 4.79 ± 0.49 mmol/l without dietary change. Pre-dialysis bicarbonate increased from 18.15 ± 1.35 to 20.27 ± 1.88 mmol/l, however with an increase in blood pressure. Nutritionally, lean tissue mass was reduced in the controls suggesting less catabolism in the intervention group. There was no change in ECGs. Limitations are small sample size and unblinded study design lacking a placebo, with several participants failing to achieve the target of 22 mmol/l serum bicarbonate levels due mainly to tablet burden. CONCLUSION Oral sodium bicarbonate reduced bicarbonate loss and potassium gain in the inter-dialytic period, and may also preserve lean tissue mass. TRIAL REGISTRATION The study was registered prospectively on 06/08/2015 with EU Clinical Trials Register EudraCT number 2015-001439-20 .
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3.
The role of potassium in atherosclerosis.
Sahranavard, T, Carbone, F, Montecucco, F, Xu, S, Al-Rasadi, K, Jamialahmadi, T, Sahebkar, A
European journal of clinical investigation. 2021;(3):e13454
Abstract
BACKGROUND Atherosclerosis (AS) is a chronic progressive inflammatory condition with a leading prevalence worldwide. Endothelial dysfunction leads to low-density lipoprotein trafficking into subendothelial space and the subsequent form of oxidized LDL (ox-LDL) within intimal layer, perpetuating the vicious cycle of endothelial dysfunction. K+ exerts beneficial effects in vascular wall by reducing LDL oxidization, vascular smooth muscle cells (VSMCs) proliferation, and free radical generation. K+ also modulates vascular tone through a regulatory effect on cell membrane potential. MATERIALS AND METHODS The most relevant papers on the association between 'potassium channels' and 'atherosclerosis' were selected among those deposited on PubMed from 1990 to 2020. RESULTS Here, we provide a short narrative review that elaborates on the role of K+ in atherosclerosis. This review also update the current knowledge about potential pharmacological agents targeting K+ channels with a special focus on pleiotropic activities of agents such as statins, sulfonylureas and dihydropyridines. CONCLUSION In this review, the mechanism of different K+ channels on vascular endothelium will be summarized, mainly focusing on their pathophysiological role in atherosclerosis and potential therapeutic application.
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4.
Potassium Metabolism and Management in Patients with CKD.
Yamada, S, Inaba, M
Nutrients. 2021;(6)
Abstract
Potassium (K), the main cation inside cells, plays roles in maintaining cellular osmolarity and acid-base equilibrium, as well as nerve stimulation transmission, and regulation of cardiac and muscle functions. It has also recently been shown that K has an antihypertensive effect by promoting sodium excretion, while it is also attracting attention as an important component that can suppress hypertension associated with excessive sodium intake. Since most ingested K is excreted through the kidneys, decreased renal function is a major factor in increased serum levels, and target values for its intake according to the degree of renal dysfunction have been established. In older individuals with impaired renal function, not only hyperkalemia but also hypokalemia due to anorexia, K loss by dialysis, and effects of various drugs are likely to develop. Thus, it is necessary to pay attention to K management tailored to individual conditions. Since abnormalities in K metabolism can also cause lethal arrhythmia or sudden cardiac death, it is extremely important to monitor patients with a high risk of hyper- or hypokalemia and attempt to provide early and appropriate intervention.
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5.
Urinary Potassium and Kidney Function Decline in the Population-Observational Study.
Cirillo, M, Bilancio, G, Cavallo, P, Palladino, R, Zulli, E, Villa, R, Veneziano, R, Laurenzi, M
Nutrients. 2021;(8)
Abstract
Background-Some data suggest favorable effects of a high potassium intake on kidney function. The present population-based study investigated cross-sectional and longitudinal relations of urinary potassium with kidney function. Methods-Study cohort included 2027 Gubbio Study examinees (56.9% women) with age ≥ 18 years at exam-1 and with complete data on selected variables at exam-1 (1983-1985), exam-2 (1989-1992), and exam-3 (2001-2007). Urinary potassium as urinary potassium/creatinine ratio was measured in daytime spot samples at exam-1 and in overnight timed collections at exam-2. Estimated glomerular filtration rate (eGFR) was measured at all exams. Covariates in analyses included demographics, anthropometry, blood pressure, drug treatments, diabetes, smoking, alcohol intake, and urinary markers of dietary sodium and protein. Results-In multivariable regression, urinary potassium/creatinine ratio cross-sectionally related to eGFR neither at exam-1 (standardized coefficient and 95%CI = 0.020 and -0.059/0.019) nor at exam-2 (0.024 and -0.013/0.056). Exam-1 urinary potassium/creatinine ratio related to eGFR change from exam-1 to exam-2 (0.051 and 0.018/0.084). Exam-2 urinary potassium/creatinine ratio related to eGFR change from exam-2 to exam-3 (0.048 and 0.005/0.091). Mean of urinary potassium/creatinine ratio at exam-1 and exam-2 related to eGFR change from exam-1 to exam-3 (0.056 and 0.027/0.087) and to incidence of eGFR < 60 mL/min per 1.73 m2 from exam-1 to exam-3 (odds ratio and 95%CI = 0.78 and 0.61/0.98). Conclusion-In the population, urinary potassium did not relate cross-sectionally to eGFR but related to eGFR decline over time. Data support the existence of favorable effects of potassium intake on ageing-associated decline in kidney function.
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6.
An evaluation of sodium zirconium cyclosilicate as a treatment option for hyperkalemia.
Takkar, C, Nassar, T, Qunibi, W
Expert opinion on pharmacotherapy. 2021;(1):19-28
Abstract
INTRODUCTION Hyperkalemia, defined as serum potassium level > 5.0 mEq/l, is associated with serious cardiac dysrhythmias, sudden death and increased mortality risk. It is common in patients with chronic kidney disease (CKD), diabetes (DM) and heart failure (HF), particularly in those treated with the renin-angiotensin-aldosterone system (RAAS) inhibitors or potassium-sparing diuretics. Although these drugs have documented renal and cardiac protective benefits, frequent hyperkalemia associated with their use often dictates administration of suboptimal doses or their discontinuation altogether. Treatment for chronic hyperkalemia in these settings has been challenging; however, the recent introduction of two new potassium-binding resins has revolutionized our approach to treating hyperkalemia. AREAS COVERED We review key clinical data relating to the pharmacokinetics, efficacy and safety of sodium zirconium cyclosilicate (SZC) as a treatment option for hyperkalemia. EXPERT OPINION SZC and Patiromer are promising new agents for lowering serum potassium in hyperkalemic patients, including those with CKD, with and without DM or HF, facilitating the use of the RAAS inhibitors for renal and cardiac protection. Recent randomized clinical trials have shown that SZC effectively lowers serum potassium and maintains normokalemia in most hyperkalemic patients. Clinical trials showed that SZC lowers serum potassium within 1 h, although it is not approved for treating acute hyperkalemia. SZC was well tolerated and associated with minimal adverse effects.
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7.
Hyperkalemia and Hypertension Post Organ Transplantation - A Management Challenge.
Hamrahian, SM, Fülöp, T
The American journal of the medical sciences. 2021;(1):106-110
Abstract
Potassium is the most important intracellular cation and the kidneys play a pivotal role in potassium homeostasis. Potassium disorder is a common electrolyte abnormality and it increases the risk of death from any cause, particularly cardiovascular events. Hyperkalemia is a common electrolyte abnormality encountered post organ transplantation. The etiology is multifactorial, and includes drugs such as calcineurin inhibitors. In certain regards, the clinical picture of post-transplantation hyperkalemia and hypertension resembles that of Gordon syndrome or familial hyperkalemic hypertension, a disorder characterized by over activity of thiazide-sensitive sodium chloride cotransporter. Effective and safe management of chronic hyperkalemia can be challenging in this special patient population. Despite the significant short-term and long-term side effects, fludrocortisone (a potent synthetic oral mineralocorticoid receptor agonist) has emerged as the default drug of choice for treatment of refractory hyperkalemia in many organ transplant recipients. However, the long-term efficacy and safety of fludrocortisone for management of hyperkalemia in organ transplant recipients remains unknown. This review discusses potassium homeostasis, including the role of the kidneys, and focuses on calcineurin inhibitor-induced hyperkalemia and on the under-appreciated role of thiazide-type diuretic use in management of hyperkalemia and hypertension. We present an illustrative case of post-transplantation hyperkalemia and hypertension with relevant literature.
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8.
Structural Insights into the Mechanisms and Pharmacology of K2P Potassium Channels.
Natale, AM, Deal, PE, Minor, DL
Journal of molecular biology. 2021;(17):166995
Abstract
Leak currents, defined as voltage and time independent flows of ions across cell membranes, are central to cellular electrical excitability control. The K2P (KCNK) potassium channel class comprises an ion channel family that produces potassium leak currents that oppose excitation and stabilize the resting membrane potential in cells in the brain, cardiovascular system, immune system, and sensory organs. Due to their widespread tissue distribution, K2Ps contribute to many physiological and pathophysiological processes including anesthesia, pain, arrythmias, ischemia, hypertension, migraine, intraocular pressure regulation, and lung injury responses. Structural studies of six homomeric K2Ps have established the basic architecture of this channel family, revealed key moving parts involved in K2P function, uncovered the importance of asymmetric pinching and dilation motions in the K2P selectivity filter (SF) C-type gate, and defined two K2P structural classes based on the absence or presence of an intracellular gate. Further, a series of structures characterizing K2P:modulator interactions have revealed a striking polysite pharmacology housed within a relatively modestly sized (~70 kDa) channel. Binding sites for small molecules or lipids that control channel function are found at every layer of the channel structure, starting from its extracellular side through the portion that interacts with the membrane bilayer inner leaflet. This framework provides the basis for understanding how gating cues sensed by different channel parts control function and how small molecules and lipids modulate K2P activity. Such knowledge should catalyze development of new K2P modulators to probe function and treat a wide range of disorders.
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9.
Potassium and phosphorus transport and signaling in plants.
Wang, Y, Chen, YF, Wu, WH
Journal of integrative plant biology. 2021;(1):34-52
Abstract
Nitrogen (N), potassium (K), and phosphorus (P) are essential macronutrients for plant growth and development, and their availability affects crop yield. Compared with N, the relatively low availability of K and P in soils limits crop production and thus threatens food security and agricultural sustainability. Improvement of plant nutrient utilization efficiency provides a potential route to overcome the effects of K and P deficiencies. Investigation of the molecular mechanisms underlying how plants sense, absorb, transport, and use K and P is an important prerequisite to improve crop nutrient utilization efficiency. In this review, we summarize current understanding of K and P transport and signaling in plants, mainly taking Arabidopsis thaliana and rice (Oryza sativa) as examples. We also discuss the mechanisms coordinating transport of N and K, as well as P and N.
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10.
Recent progress in understanding salinity tolerance in plants: Story of Na+/K+ balance and beyond.
Hussain, S, Hussain, S, Ali, B, Ren, X, Chen, X, Li, Q, Saqib, M, Ahmad, N
Plant physiology and biochemistry : PPB. 2021;:239-256
Abstract
High salt concentrations in the growing medium can severely affect the growth and development of plants. It is imperative to understand the different components of salt-tolerant network in plants in order to produce the salt-tolerant cultivars. High-affinity potassium transporter- and myelocytomatosis proteins have been shown to play a critical role for salinity tolerance through exclusion of sodium (Na+) ions from sensitive shoot tissues in plants. Numerous genes, that limit the uptake of salts from soil and their transport throughout the plant body, adjust the ionic and osmotic balance of cells in roots and shoots. In the present review, we have tried to provide a comprehensive report of major research advances on different mechanisms regulating plant tolerance to salinity stress at proteomics, metabolomics, genomics and transcriptomics levels. Along with the role of ionic homeostasis, a major focus was given on other salinity tolerance mechanisms in plants including osmoregulation and osmo-protection, cell wall remodeling and integrity, and plant antioxidative defense. Major proteins and genes expressed under salt-stressed conditions and their role in enhancing salinity tolerance in plants are discussed as well. Moreover, this manuscript identifies and highlights the key questions on plant salinity tolerance that remain to be discussed in the future.