Abundant Cation Research Articles

Study of Serum Magnesium, Potassium and Calcium in Acute Myocardial Infarction Patients

Introduction: A myocardial infarction happens when blood flow stops or decreases to the coronary arteries of the myocardial muscle, resulting in damage to the heart muscle. Magnesium is important electrolyte plays vital role in suppressing arrhythmias during myocardial ischemia and during reperfusion. Potassium is the most abundant cation of intracellular fluid. A significant correlation between hypokalemia and ventricular fibrillation is recorded. Calcium plays a vital role in myocardial muscle contraction. Aim: To study serum levels of magnesium, potassium and calcium in acute myocardial infarction patients. Material and methods: This was a prospective case control study conducted in Prathima Institute of medical sciences Nagunur, Karimnagar, Telangana state, India between January 2015 to December 2015. A total 50 acute myocardial infarction patients and 50 normal age and sex matched healthy controls selected for study. Serum magnesium estimated by colorimetric xylidyl blue complex method, serum potassium estimated by ion selective electrode method and serum calcium by OCPC method. Statistical analysis carried out using statistical software SPSS version 16 and p-value < 0.05 considered statistically significant. Results: Serum levels of magnesium, potassium and calcium were significantly decreased in acute myocardial infarction patients when compared healthy controls and is statistically significant (<0.05) Conclusion: The above study suggested decreased serum level of key elements such as magnesium, potassium and calcium in acute myocardial infarction patients when compared to healthy controls. Estimation and correction of these elements may play a pivotal role in management of patients with acute myocardial infarction

Assessment of dietary magnesium intake in the Eastern Province of Saudi Arabia.

Magnesium is an essential element and the most abundant intracellular cation after potassium. This cross-sectional study assessed the average dietary magnesium intake among residents of the Eastern Province of Saudi Arabia. Data was collected using a self-reported validated electronic questionnaire between April 2022 and July 2023. The first part of the survey included demographic data, and the second section comprised 33 items, including a semi-quantitative tool specifically designed to evaluate magnesium intake over the last three months. We included 1065 participants, out of whom 61.1% were women. The predominant age group was 19 - 26 years (56.9%), and most participants (83.3%) reported no comorbidities. The majority (48.5%) had normal weight, 246 (23%) were overweight, and 193 (18.1%) were obese. Most participants had low dietary magnesium intake, ranging from one to five times monthly. There was a positive correlation between age and dietary magnesium consumption. The study highlights a concerning trend of low magnesium intake, representing a risk for various chronic diseases. This trend could be linked to increased consumption of typical diets low in magnesium, such as those high in refined sugars, flour, and processed foods, prevalent among the younger Saudi population.

Characterization of a novel MgtE homolog and its structural dynamics in membrane mimetics

Magnesium (Mg2+) is the most abundant divalent cation in the cell and is critical for numerous cellular processes. Despite its importance, the mechanisms of intracellular Mg2+ transport and its regulation are poorly understood. MgtE is the main Mg2+ transport system in almost half of bacterial species and is an ortholog of mammalian SLC41A1 transporters, which are implicated in neurodegenerative diseases and cancer. To date, only MgtE from Thermus thermophilus (MgtETT) has been extensively characterized, mostly in detergent micelles, and gating-related structural dynamics in biologically relevant membranes are scarce. The MgtE homolog from Bacillus firmus (MgtEBF) is unique since it lacks the entire Mg2+-sensing N-domain but has conserved structural motifs in the TM-domain for Mg2+ transport. In this work, we have successfully purified this novel homolog in a stable and functional form, and ColabFold structure prediction analysis suggests a homodimer. Further, microscale thermophoresis experiments show that MgtEBF binds Mg2+ and ATP, similar to MgtETT. Importantly, we show that, despite lacking the N-domain, MgtEBF mediates Mg2+ transport function in the presence of an inwardly directed Mg2+ gradient in reconstituted proteoliposomes. Furthermore, comparison of the organization and dynamics of Trp residues in the TM-domain of MgtEBF in membrane mimetics, in apo- and Mg2+-bound forms, suggests that the cytoplasmic binding of Mg2+ might involve modest gating-related conformational changes at the TM-domain. Overall, our results show that the gating-related structural dynamics (hydration dynamics, conformational heterogeneity) of the full-length MgtEBF is significantly changed in functionally pertinent membrane environment, emphasizing the importance of lipid-protein interactions in MgtE gating mechanisms.

DNAR-11. NUCLEAR POTASSIUM GOVERNS NUCLEAR ENVELOPE INTEGRITY AND GENOMIC STRUCTURE IN MEDULLOBLASTOMA

Abstract Potassium is the most abundant intracellular cation with crucial functions such as regulating cell proliferation, migration, and differentiation. Potassium flux across cellular membranes is controlled by potassium channels. While the role of cytosolic potassium has been researched for many decades, very little is known about the modulation or significance of potassium in the cell nucleus. Here, we identify potassium channel subunit KCNG1 as a novel regulator of nuclear potassium in medulloblastoma (MB), the most common malignant pediatric brain tumour. Using genetically encoded Förster resonance energy transfer (FRET)-based potassium sensors, we show that KCNG1 regulates nuclear potassium level independently of cytosolic potassium level. KCNG1 knockdown alters the genomic architecture of MB cells by stabilizing G-quadruplex (G4) DNA, inducing DNA damage, and reducing nuclear envelope-associated heterochromatin. Ultimately, KCNG1 deficiency results in nuclear swelling, thereby compromising nuclear envelope integrity and inducing DNA spillage into the cytosol to activate the pro-inflammatory cGAS/STING pathway. Genetic knockdown of KCNG1 mitigates tumour growth and prolongs the survival of mice bearing MB of distinct subgroups. Altogether, our findings reveal that nuclear potassium regulates genomic structure and nuclear envelope integrity and demonstrate that targeting a nuclear potassium channel can be leveraged to activate immunogenic signalling in MB.

A meta-analysis highlights globally widespread potassium limitation in terrestrial ecosystems.

Potassium (K+ ) is the most abundant inorganic cation in plant cells, playing a critical role in various plant functions. However, the impacts of K on natural terrestrial ecosystems have been less studied compared with nitrogen (N) and phosphorus (P). Here, we present a global meta-analysis aimed at quantifying the response of aboveground production to K addition. This analysis is based on 144 field K fertilization experiments. We also investigate the influences of climate, soil properties, ecosystem types, and fertilizer regimes on the responses of aboveground production. We find that: K addition significantly increases aboveground production by 12.3% (95% CI: 7.4-17.5%), suggesting a widespread occurrence of K limitation across terrestrial ecosystems; K limitation is more prominent in regions with humid climates, acidic soils, or weathered soils; the effect size of K addition varies among climate zones/regions, and is influenced by multiple factors; and previous N : K and K : P thresholds utilized to detect K limitation in wetlands cannot be applied to other biomes. Our findings emphasize the role of K in limiting terrestrial productivity, which should be integrated into future terrestrial ecosystems models.

Synthesis of CuCo2S4@Expanded Graphite with crystal/amorphous heterointerface and defects for electromagnetic wave absorption

The remarkable advantages of heterointerface and defect engineering and their unique electromagnetic characteristics inject infinite vitality into the design of advanced carbon-matrix electromagnetic wave absorbers. However, understanding the interface and dipole effects based on microscopic and macroscopic perspectives, rather than semi-empirical rules, can facilitate the design of heterointerfaces and defects to adjust the impedance matching and electromagnetic wave absorption of the material, which is currently lacking. Herein, CuCo2S4@Expanded Graphite heterostructure with multiple heterointerfaces and cation defects are reported, and the morphology, interfaces and defects of component are regulated by varying the concentration of metal ions. The results show that the 3D flower-honeycomb morphology, the crystal-crystal/amorphous heterointerfaces and the abundant cation defects can effectively adjust the conductive and polarization losses, achieve the impedance matching balance of carbon materials, and improve the absorption of electromagnetic wave. For the sample CEG-6, the effective absorption of Ku band with RLmin of −72.28 dB and effective absorption bandwidth of 4.14 GHz is realized at 1.4 mm, while the filler loading is only 7.0 wt. %. This article reports on the establishment of potential relationship between crystal-crystal/amorphous heterointerfaces, cation defects, and the impedance matching of carbon materials.

Beyond Ion Homeostasis: Hypomagnesemia, Transient Receptor Potential Melastatin Channel 7, Mitochondrial Function, and Inflammation.

As the second most abundant intracellular divalent cation, magnesium (Mg2+) is essential for cell functions, such as ATP production, protein/DNA synthesis, protein activity, and mitochondrial function. Mg2+ plays a critical role in heart rhythm, muscle contraction, and blood pressure. A significant decline in Mg2+ intake has been reported in developed countries because of the increased consumption of processed food and filtered/deionized water, which can lead to hypomagnesemia (HypoMg). HypoMg is commonly observed in cardiovascular diseases, such as heart failure, hypertension, arrhythmias, and diabetic cardiomyopathy, and HypoMg is a predictor for cardiovascular and all-cause mortality. On the other hand, Mg2+ supplementation has shown significant therapeutic effects in cardiovascular diseases. Some of the effects of HypoMg have been ascribed to changes in Mg2+ participation in enzyme activity, ATP stabilization, enzyme kinetics, and alterations in Ca2+, Na+, and other cations. In this manuscript, we discuss new insights into the pathogenic mechanisms of HypoMg that surpass previously described effects. HypoMg causes mitochondrial dysfunction, oxidative stress, and inflammation. Many of these effects can be attributed to the HypoMg-induced upregulation of a Mg2+ transporter transient receptor potential melastatin 7 channel (TRMP7) that is also a kinase. An increase in kinase signaling mediated by HypoMg-induced TRPM7 transcriptional upregulation, independently of any change in Mg2+ transport function, likely seems responsible for many of the effects of HypoMg. Therefore, Mg2+ supplementation and TRPM7 kinase inhibition may work to treat the sequelae of HypoMg by preventing increased TRPM7 kinase activity rather than just altering ion homeostasis. Since many diseases are characterized by oxidative stress or inflammation, Mg2+ supplementation and TRPM7 kinase inhibition may have wider implications for other diseases by acting to reduce oxidative stress and inflammation.

Association of serum magnesium levels with seizure disorder; experience from central India

Magnesium is the fourth most abundant cation in the body. It has several functions in the human body including its role as a cofactor for more than 300 enzymatic reactions. Mg is a potential modulator of seizure activity because of its ability to antagonize the excitatory calcium influx through the N-methyl-D-aspartate receptor. Low magnesium levels in people with refractory epilepsy can increase the frequency of seizures. Hence in our study we aim to study the association of serum magnesium levels with seizure disorders and compare it with matched controls. In our study 154 adult individuals were included with seizure patients to control ratio of 1:1. Serum Magnesium levels was estimated in all individuals and levels were compared between patients of seizure disorder and healthy controls. Mean serum magnesium level was significantly lower in patients of seizure disorder as compared to controls (p<0.01). We, also observed significantly lower calcium level amongst cases as compared to controls (p<0.05). The mean magnesium level within 24 hours of seizures was 1.47±0.50 mg/dl whereas as the duration since seizures increased, mean magnesium level increased. In our study we found significant association between seizures and serum magnesium levels, as low magnesium has been implicated in refractory seizures which are resistant to anti-epileptic drugs and magnesium supplementation in such patients may result in decrease in number of anti-epileptic drugs and better control of seizures.

Quantum dot heterostructures on N-doped graphene with accelerated diffusion kinetics for stable lithium-ion storage

The high energy density and low self-discharge rate of lithium-ion batteries make them promising for large-scale energy storage. However, the practical development of such electrochemical energy storage systems relies heavily on the development of anode materials with high multiplier capacity and stable cycle life. Here, a simple and efficient one-step hydrothermal method is used to obtain stannide heterostructures, which are loaded on N-doped graphene (SnS2/SnO2@NG) that promotes Li+ diffusion for fast charge transfer. It is demonstrated that the built-in electric field generated by the electron transfer from electron-rich SnS2 to SnO2 in the stannide heterojunction collectively provides abundant cation adsorption sites, accelerating the migration of Li+ thus improving the electrochemical reaction kinetics. Besides, the SnS2/SnO2 nanoparticles have high structural stability, and the heterojunction compressive stresses obtained from density functional theory (DFT) calculations can significantly limit the structural damage. When applied as anodes in Li+ batteries with 300 cycles at 0.5 A/g, we achieved a high reversible capacity of 892.73 mAh/g. The rational design of low-cost batteries for energy storage and conversion can benefit from the quantitative design of fast and persistent charge transfer in a stannide heterostructure.

Magnesium transporter CsMGT10 of tea plants plays a key role in chlorosis leaf vein greening

Magnesium (Mg2+), as the central atom of chlorophyll, is the most abundant divalent cation for plant growth and development in living cells. MRS2/MGT magnesium transporters play important roles in coping with magnesium stress, chloroplast development and photosynthesis. However, the molecular mechanism of MGT influencing tea plant leaf vein color remains unknown. Here, we demonstrate that CsMGT10 may be a potential transporter influencing leaf vein color. CsMGT10 belongs to Clade A member of MRS2/MGT family. CsMGT10 has the highest expression level in leaves of tea plants. And it is mainly expressed in aboveground parts, especially in vascular bundles. Moreover, CsMGT10 localizes to the chloroplast envelope of tea plants with a high affinity to Mg2+. And the GMN motif is required for its magnesium transport function. Ectopic expression of CsMGT10 in Arabidopsis leaf variegation mutant var5-1 can restore green color of chlorosis leaf veins, and the contents of chlorophyll and carotenoid change significantly, proving its essential role in leaf vein greening. Furthermore, the chlorophyll and carotenoid of tea leaves treated with CsMGT10 antisense oligonucleotides also decrease significantly. Our findings indicate that CsMGT10 mainly acts as Mg2+ transporter in chloroplast envelope of leaf veins, which may play a key role in leaf vein greening of tea plants.

New insights into the structure and function of CNNM proteins.

Magnesium (Mg2+ ) is the most abundant divalent cation in cells and plays key roles in almost all biological processes. CBS-pair domain divalent metal cation transport mediators (CNNMs) are a newly characterized class of Mg2+ transporters present throughout biology. Originally discovered in bacteria, there are four CNNM proteins in humans, which are involved in divalent cation transport, genetic diseases, and cancer. Eukaryotic CNNMs are composed of four domains: an extracellular domain, a transmembrane domain, a cystathionine-β-synthase (CBS)-pair domain, and a cyclic nucleotide-binding homology domain. The transmembrane and CBS-pair core are the defining features of CNNM proteins with over 20 000 protein sequences known from over 8000 species. Here, we review the structural and functional studies of eukaryotic and prokaryotic CNNMs that underlie our understanding of their regulation and mechanism of ion transport. Recent structures of prokaryotic CNNMs confirm the transmembrane domain mediates ion transport with the CBS-pair domain likely playing a regulatory role through binding divalent cations. Studies of mammalian CNNMs have identified new binding partners. These advances are driving progress in understanding this deeply conserved and widespread family of ion transporters.

P180 EXTREMELY WIDE QRS TACHYCARDIA IN SEVERE HYPERKALEMIA: THE IMPORTANCE OF MONITORING MRA THERAPY

Abstract Although uncommon in the general population, hyperkalemia can affect up to 50% of patients with heart failure who are receiving MRA and/or are affected by CKD . Since potassium is the most abundant intracellular cation, hyperkaliemia causes a profound change in action potential, which manifests as expected electrocardiographic changes (lower voltage P wave, AV block, wide QRS, high voltage T wave) and arrhythmias. Clinic case. A 77–year–old woman was admitted to ED for dyspnea. She had a medical history of stage 3 CKD and a HFrEF with a recent admission in medical department for worsening congestion, from which was dimitted with a supratherapeutic dose of MRA (canrenone 300 mg/die). Physical examination at the admission excluded signs of central or peripheral congestion . An EKG was performed and revealed an heart rate of 95 beats per minute and extremely wide QRS (280 ms). Contextually, a blood gas analysis showed high potassium level (K 9 mmol/l) and metabolic acidosis. Due to the inability to demonstrate the presence of P wave and a regular A–V conduction, a differential diagnosis between a VT and a SVT with a wide QRS was required. The presence of a fusion beat, a negative concordance of QRS in the precordials derivation, and an extreme right axis deviation led to a diagnosis of slow VT. Cuncurrently with the onset of hyperkalemia therapy, an ECV with sinus rhythm restoration was done. The following EKGs showed expected electrical changes based on the measured potassium level. After ECV with K 8 mmol/l: QRS remained wide (180ms) with an heart rate of 65 beats per minute in the presence of possible junctional rhythm or sino–ventricular rhythm, which is sometimes described in hyperkalemia as an expression of atrial inectability with the exception of the conduction fibers. After 1 hour with K 6.3 mmol/l: QRS of normal duration with an HR of 60 bpm and a sinus rhythm but with low voltage P wave and concomitant AV block of I grade that was gradually restored with the normalization of potassium levels after canrenone suspension. Because the numerous side effects of hyperkaliemia careful monitoring of MRA therapy and potassium level plays a critical role in the prevention and diagnosis of arrhythmias and EKG changes in patients with HFrEF.

Comparative analysis of serum magnesium level in diabetic and non-diabetics presented with acute myocardial infarction

Background: Serum concentrations of electrolytes have been shown to change with plasma glucose levels. Magnesium, the second most abundant intracellular cation plays a key role in cellular metabolism. The level of glycemic control is found to be inversely proportional to magnesium deficiency.
 Objectives: To assess the changes in serum magnesium level between T2DM and non-diabetic patients presented with acute myocardial infarction.
 Material & Methods: This cross sectional research was carried out at cardiac care centre of teaching hospital of Lahore from June to December 2020. In this study overall 200 T2DM and non-diabetic patients aged 20-60 years of either gender were inducted via non probability sampling technique. These patients were presented in emergency with acute myocardial infarction within 12 hours from the beginning of symptoms determined by history and medical records. Serum magnesium level between two groups was compared by t-test. The difference was considered significant with p value <0.05.
 Results: The mean age among study participants was 52.72±6.24 years. The majority 70% of the participants were male while 30% were female. Group A comprised of 110(55%) type 2 diabetic patients while group B comprised of 90(45%) non diabetic patients with acute myocardial infarction. Mean serum magnesium level of the study participants was 1.56±0.42 mg/dl. Mean serum magnesium level in group A was 1.25-0.42 mg/dl and in group B was 1.84-0.32 mg/dl. Mean serum magnesium level was significantly lowered in group A (diabetics) as compared to group B (non-diabetics) with p-value=0.000. Study found that low serum magnesium level showed significant association with age, gender, glycemic control and diabetes duration with p-value=0.000. 
 Conclusion: In comparison with non-diabetic patients, serum magnesium level was significantly lowered in diabetic patients presented with acute myocardial infarction. Hypomagnesaemia was directly related to age, gender, glycemic control and duration of diabetes.
 Keywords: Magnesium level, T2DM, Acute Myocardial Infarction, Glycemic control

Goldilocks and RNA: where Mg2+ concentration is just right.

Magnesium, the most abundant divalent cation in cells, catalyzes RNA cleavage but also promotes RNA folding. Because folding can protect RNA from cleavage, we predicted a 'Goldilocks landscape', with local maximum in RNA lifetime at Mg2+ concentrations required for folding. Here, we use simulation and experiment to discover an innate and sophisticated mechanism of control of RNA lifetime. By simulation we characterized RNA Goldilocks landscapes and their dependence on cleavage and folding parameters. Experiments with yeast tRNAPhe and the Tetrahymena ribozyme P4-P6 domain show that structured RNAs can inhabit Goldilocks peaks. The Goldilocks peaks are tunable by differences in folded and unfolded cleavage rate constants, Mg2+ binding cooperativity, and Mg2+ affinity. Different folding and cleavage parameters produce Goldilocks landscapes with a variety of features. Goldilocks behavior allows ultrafine control of RNA chemical lifetime, whereas non-folding RNAs do not display Goldilocks peaks of protection. In sum, the effects of Mg2+ on RNA persistence are expected to be pleomorphic, both protecting and degrading RNA. In evolutionary context, Goldilocks behavior may have been a selectable trait of RNA in an early Earth environment containing Mg2+ and other metals.

Defect-Rich NiFeAl-Layered Double Hydroxide Nanosheets for Efficient Electrocatalytic Oxygen Evolution Reaction

Atomic-level defect engineering is effective in optimizing the performance of transition metal-based catalytic materials. In this work, ultrathin 3 nm NiFeAl layered double hydroxide (NiFeAl-LDHs) nanosheets with rich cation vacancies were grown on nickel foam by a fast microwave-assisted process for the oxygen evolution reaction. The defect-rich NiFeAl-LDHs (D-NiFeAl-LDHs/NF) show an excellent overpotential (207 mV) and a Tafel slope (34 mV dec–1) at 10 mA cm–2. Experimental results and theoretical calculations show that the introduction of abundant cation vacancies effectively adjusts the electronic structure around reaction sites and optimizes the adsorption strength of reaction intermediates, thus significantly improving the oxygen evolution reaction catalytic performance.

Spatial-Temporal Characteristics and Influencing Factors of Lake Water and Groundwater Chemistry in Hulun Lake, Northeast China

Lakes in cold and arid regions are extremely vulnerable to global climate change, and the study of seasonal spatial and temporal fluctuations of lake-groundwater chemistry is of major significance for water resource management and environmental preservation. In this study, we combined hydrogeochemical, multivariate statistical, and spatial interpolation methods to assess spatial and temporal variations of lake and groundwater chemistry in Hulun Lake during the frozen and non-frozen periods. The results show that sodium (Na+) is the most abundant cation in the Hulun Lake area. Bicarbonate (HCO3−) and sulfate (SO42−) are the most predominant anions in the lake, river, and ground water during both seasons. The higher Na+ + K+ concentrations in the frozen season were related to longer circulation time and lower renewable rate. The water chemistry of the lake was of the HCO3-SO4-Cl-Na type and that of groundwater in the east and west regions was of the SO4-Cl-Na and HCO3-Na types, respectively. The chemical compositions of groundwater in the non-frozen season were mainly affected by evaporation and concentration, while rock weathering, evaporation, and human activities jointly controlled groundwater chemical component in the frozen period. Based on hierarchical cluster analysis (HCA) and principal component analysis (PCA) methods, Ca2+, NO3−, and SO42− were identified as the main controlling indicators of the chemical characteristics of groundwater and lake water. The increase of Ca2+ concentration in the center of the lake was related to groundwater discharge along the marginal tectonic fracture zone along the lake shores, which was the potential groundwater discharge area. The unconsolidated aquifer provides recharge channels for groundwater on the eastern side, which has a certain influence on the increase of nutrient concentration (NO3−) in the lake on the eastern shore. This research adds to our rough understanding of the lake-groundwater interaction in Hulun Lake, and provides a scientific foundation for the sustainable use of water resources, as well as the eco-logical integrity preservation in cold and arid regions.

The Prevalence of Hypomagnesemia in Critically Ill Patients Admitted in Medically Intensive Care Unit

Background Magnesium is the fourth most abundant cation in the human body. Hypomagnesemia can result from decreased intake, redistribution of magnesium from the extracellular to the intracellular space, or increased renal or gastrointestinal loss. Hypomagnesemia can cause severe outcomes in ill patients. So, we conducted this study to determine the frequency of hypomagnesemia in critically ill medical patients. Methods This is a Descriptive cross-sectional study involving 120 patients admitted in the medical intensive care unit (MICU) of the Holy Family Hospital, Rawalpindi, Pakistan. The study was conducted from July 2020 to September 2021. About 1 ml sample of blood was taken from each patient included and sent to the hospital laboratory for evaluation of serum magnesium levels. All the collected data was entered and analyzed on SPSS v. 23. A p-value of ≤ 0.05 was taken significant. Results In our study, the mean age of the patients was 42.76±12.77 years, and the male-to-female ratio of the patients was 1:1. The mean value of the APACHE II score of the patients was 29.68±2.571. Hypomagnesemia was found in 28 (23.33%) patients. Conclusion According to our study, the frequency of hypomagnesemia in critically ill medical patients was 23.33% (28 patients).

Magnesium Homeostasis: Lessons from Human Genetics.

Mg 2+ , the fourth most abundant cation in the body, serves as a cofactor for about 600 cellular enzymes. One third of ingested Mg 2+ is absorbed from the gut through a saturable transcellular process and a concentration-dependent paracellular process. Absorbed Mg 2+ is excreted by the kidney and maintains serum Mg 2+ within a narrow range of 0.7-1.25 mmol/L. The reabsorption of Mg 2+ by the nephron is characterized by paracellular transport in the proximal tubule and thick ascending limb. The nature of the transport pathways in the gut epithelia and thick ascending limb has emerged from an understanding of the molecular mechanisms responsible for rare monogenetic disorders presenting with clinical hypomagnesemia. These human disorders due to loss-of-function mutations, in concert with mouse models, have led to a deeper understanding of Mg 2+ transport in the gut and renal tubule. This review focuses on the nature of the transporters and channels revealed by human and mouse genetics and how they are integrated into an understanding of human Mg 2+ physiology.

Structural basis for CorA channel gating using conformation-specific synthetic antigen binders and single-particle cryo-EM.

The magnesium ion (Mg2+) is an abundant divalent cation in living cells, and plays a significant role in many biological processes, including energy metabolism, protein production, nucleotide replication and transcription, and muscle contraction. In prokaryotes CorA is the primary channel for Mg2+ uptake, and functionally complements the mitochondrial magnesium channel, Mrs2, whose dysfunction leads to cell death. Here we employ two different conformation-specific synthetic antigen binders (sABs) and single-particle cryo-EM to solve the structures of nanodisc-reconstituted T. maritima CorA in desaturating amounts of Mg2+ and in the complete absence of magnesium to resolutions of 3.1-3.4Å. We generated these sABs using a phage display library and competitive selections. We show CorA is nearly continuously variable in conformation when magnesium is even slightly depleted, but that discrete conformers can be isolated from our cryo-EM datasets due to our sAB-based approach. The resolutions in our dataset greatly improve on earlier cryo-EM studies, and these high-resolution structures represent the first ones in lipid-filled nanodiscs. These data show two major conformational changes as magnesium is depleted from regulatory cytoplasmic binding sites. One, the rearrangement of the cytoplasmic N-terminal regulatory region due to the absence of bound Mg2+, driven both by charge-based repulsion and compensating interactions. Two, concerted molecular motions driven by electrostatic interactions, leading to dilation of the pore and ostensibly channel activation. We also describe a conformational ensemble, with a population size inversely proportional to environmental [Mg2+], where both apparently inactive and active conformers present in equilibrium. Our new model shows CorA exists as metastable states in solution, with a stochastic relationship between open and closed channels, rather than a traditional deterministic mechanism. We believe our study provides a new template for understanding magnesium homeostasis in homologous systems.

Mechanisms of paracellular transport of magnesium in intestinal and renal epithelia.

Magnesium is the fourth most abundant cation in the body. It plays a critical role in many biological processes, including the process of energy release. Paracellular transport of magnesium is mandatory for magnesium homeostasis. In addition to intestinal absorption that occurs in part across the paracellular pathway, magnesium is reabsorbed by the kidney tubule. The bulk of magnesium is reabsorbed through the paracellular pathway in the proximal tubule and the thick ascending limb of the loop of Henle. The finding that rare genetic diseases due to pathogenic variants in genes encoding specific claudins (CLDNs), proteins located at the tight junction that determine the selectivity and the permeability of the paracellular pathway, led to an awareness of their importance in magnesium homeostasis. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is caused by a loss of function of CLDN16 or CLDN19. Pathogenic CLDN10 variants cause HELIX syndrome, which is associated with a severe renal loss of sodium chloride and hypermagnesemia. The present review summarizes the current knowledge of the mechanisms and factors involved in paracellular magnesium permeability. The review also highlights some of the unresolved questions that need to be addressed.