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Noise-induced hearing loss (NIHL) is a significant clinical, social, and economic issue. The development of novel therapeutic agents to reduce NIHL will potentially benefit multiple very large noise-exposed populations. Oxidative stress has been identified as a significant contributor to noise-induced sensory cell death and NIHL, and several antioxidant strategies have now been suggested for potential translation to human subjects. One such strategy is a combination of beta-carotene, vitamins C and E, and magnesium, which has shown promise for protection against NIHL in rodent models, and is being evaluated in a series of international human clinical trials using temporary (military gunfire, audio player use) and permanent (stamping factory, military airbase) threshold shift models (NCT00808470). The noise exposures used in the recently completed Swedish military gunfire study described in this report did not, on average, result in measurable changes in auditory function using conventional pure-tone thresholds and distortion product otoacoustic emission (DPOAE) amplitudes as metrics. However, analysis of the plasma samples confirmed significant elevations in the bloodstream 2 hours after oral consumption of active clinical supplies, indicating the dose is realistic. The plasma outcomes are encouraging, but clinical acceptance of any novel therapeutic critically depends on demonstration that the agent reduces noise-induced threshold shift in randomized, placebo-controlled, prospective human clinical trials. Although this noise insult did not induce hearing loss, the trial design and study protocol can be applied to other populations exposed to different noise insults.

The binding of Mg(2+) with the Euplotes octocarinatus centrin (EoCen) and the effect of Mg(2+) on the binding of EoCen with the peptide melittin were examined by spectroscopic methods. In this study, it was found that Mg(2+) may bind with Ca(2+)-binding sites, at least partly, on EoCen, which displays ∼10-fold weaker affinity than Ca(2+). In the presence of Mg(2+), Ca(2+)-saturated EoCen undergoes significant conformational changes resulting in decreased exposure of hydrophobic surfaces on the protein. Additionally, excess Mg(2+) did not change the stoichiometry, but rather reduced the affinity of EoCen to melittin. The Mg(2+)-dependent decrease in the affinities of EoCen to melittin is an intrinsic property of Mg(2+), rather than a nonspecific ionic effect. The inhibitory effect of Mg(2+) on the formation of complexes between EoCen and melittin may contribute to the specificity of EoCen in target activation in response to cellular Ca(2+) concentration fluctuations., (Copyright © 2011. Published by Elsevier B.V.)

Objective: The determination of serum magnesium levels in migraine., Methods: In a case control study performed between January 2007 and December 2007 at Tabriz University of Medical Sciences, Tabriz, Iran, 140 migraine patients were enrolled and their level of serum magnesium was determined and the results were compared with 140 healthy people who did not have any headache, kidney, or gastrointestinal disorders, and no consumption of magnesium complements., Results: Migraine patients (22 male, 118 female) with a mean age of 33.82+/-10.31 and 140 healthy people (26 male, 114 female) with a mean age of (34.19+/-9.95) were enrolled. Forty patients had aura and 100 patients did not have aura. The average serum magnesium level in the patient group (26.14+/-4.3) was significantly lower than the control (31.09+/-4.32) group (p=0.000). There was no significant difference between the mean level of serum magnesium in patients with migraine with aura and without aura, however, there was a significant linear relationship between the amount of serum magnesium and the frequency of headache., Conclusion: Serum magnesium in migraine patients was significantly lower than the normal population and related to the frequency of migraine attacks, supporting the use of magnesium in prevention and treatment of migraine.

In the retina, light onset hyperpolarizes photoreceptors and depolarizes ON bipolar cells at the sign inverting photoreceptor-ON bipolar cell synapse. Transmission at this synapse is mediated by a signaling cascade comprised of mGluR6, a G-protein containing G(αo), and the cation channel TRP melastatin 1 (TRPM1). This system is thought to be common to both the rod- and ON-cone-driven pathways, which control vision under scotopic and photopic conditions, respectively. In this study, we present evidence that the rod pathway is uniquely susceptible to modulation by PKCα at the rod-rod bipolar cell synapse. Decreased production of DAG (an activator of PKC) by inhibition of PIP₂ (phosphatidylinositol-4,5-bisphosphate) hydrolysis caused depression of the TRPM1 current. Conversely, addition of a DAG analog, 2-acetyl-1-oleoyl-sn-glycerol (OAG), potentiated the current in rod bipolar cells but not in ON-cone bipolar cells. The potentiating effects of OAG were absent both in mutant mice that lack PKCα expression and in wild-type mice in which enzymatic activity of PKCα was pharmacologically inhibited. In addition, we found that, like other members of the TRPM subfamily, TRPM1 current is susceptible to voltage-independent inhibition by intracellular magnesium, and that modulation by PKCα relieves this inhibition, as the potentiating effects of OAG are absent in low intracellular magnesium. We conclude that activation of PKCα initiates a modulatory mechanism at the rod-rod bipolar cell synapse whose function is to reduce inhibition of the TRPM1 current by magnesium, thereby increasing the gain of transmission at this synapse.

Background: Magnesium modulates insulin-mediated glucose uptake but data regarding its role in insulin secretion are scarce; therefore, in this study we determined whether decreased serum magnesium levels are associated with the impairment of insulin secretion in non-diabetic individuals., Methods: A total of 182 apparently healthy subjects, men and non-pregnant women, 18-65 years of age, were enrolled in a population-based cross-sectional study and allocated to groups with hypomagnesaemia and normomagnesaemia. The groups in the study were subsequently stratified according to glucose status: normal glucose tolerance, impaired fasting glucose, and impaired glucose tolerance. Insulin secretion was evaluated by the first and second phases of insulin secretion., Results: The Spearman coefficient between serum magnesium and the first and second phases of insulin secretion showed a significant positive correlation in the overall (r = 0.265, p < 0.0005; r = 0.541, p < 0.0005), normal glucose tolerance (r = 0.369, p = 0.001; r = 0.618, p < 0.0005), impaired fasting glucose (r = 0.320, p = 0.02; r = 0.449, p = 0.001), and impaired glucose tolerance (r = 0.129, p = 0.37; r = 0.522, p < 0.0005) groups. The multivariate linear regression analysis showed a significant association between serum magnesium levels and the first and second phases of insulin secretion: for the entire groups [B = 75.2; 95% confidence interval (CI) 27.6-122.7; B = 25.4; 95% CI 16.4-34.3], normal glucose tolerance (B = 129.6, 95% CI 38.1-221.1; B = 40.3, 95% CI 23.7-56.8), impaired fasting glucose (B = 75.2, 95% CI 27.6-122.7; B = 15.1, 95% CI 4.2-30.2), and impaired glucose tolerance (B = 57.4, 95% CI 23.5-138.3; B = 25.4, 95% CI 16.4-34.3) groups., Conclusions: Our results show that hypomagnesaemia is associated with the decrease of the first and second phases of insulin secretion in non-diabetic subjects with hypomagnesaemia., (Copyright © 2011 John Wiley & Sons, Ltd.)

We investigated the effects of changing the extracellular potassium as well as magnesium concentration ([K+]₀ and [Mg²+]₀) in cerebral penetrating arterioles. The internal diameter of isolated pressurized cerebral penetrating arterioles in rat was measured under the microscope in the low [K+]₀, low [Mg²+]₀ and high [Mg²+]₀, respectively. Vascular responses induced by the low [K+]₀ were observed in the absence and presence of several inhibitors. The low [K+]₀ produced a biphasic response consisting of an initial transient constriction followed by dilation. The transient constriction was attenuated by Na+-K+-adenosine triphosphatase (ATPase) inhibitor in a concentration-dependent manner and L-type Ca²+ channel inhibitor but not by all K+ channel inhibitors. The low [Mg²+]₀ significantly induced constriction, whereas the high [Mg²+]₀ induced dilation. We analyzed that transient constriction in the low [K+]₀ may be led by membrane depolarization induced by inactivity in Na+-K+-ATPase. The vasomotor responses of the changing of [K+]₀ as well as [Mg²+]₀ in a cerebral microcirculation may influence the pathological and therapeutic condition in cerebrovascular diseases, and may provide new therapeutic targets., (Copyright © 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

Magnesium plays a fundamental role in many cellular functions, and thus there is increasing interest in its role in clinical medicine. Although numerous experimental studies indicate positive effects of magnesium in a variety of disease states, large clinical trials often give conflicting results. However, there is clear evidence for magnesium to benefit patients with eclampsia or torsades de pointes arrhythmias. In addition, magnesium seems to have antinociceptive and anesthetic as well as neuroprotective effects, yet well-designed large clinical trials are required to determine its actual efficacy in pain management or in the state of stroke or subarachnoid hemorrhage. The current review aims to provide an overview of current knowledge and available evidence with respect to physiologic aspects of magnesium and proposed indications and recommendations for its use in the clinical setting.

TRPM7 (transient receptor potential melastatin 7) is a Ca²+- and Mg²+-permeant ion channel in possession of its own kinase domain. As a kinase, the protein has been linked to the control of actomyosin contractility, whereas the channel has been found to regulate cell adhesion as well as cellular Mg²+ homoeostasis. In the present study we show that depletion of TRPM7 by RNA interference in fibroblasts alters cell morphology, the cytoskeleton, and the ability of cells to form lamellipodia and to execute polarized cell movements. A pulldown-purification assay revealed that knockdown of TRPM7 prevents cells from activating Rac and Cdc42 (cell division cycle 42) when stimulated to migrate into a cellular wound. Re-expression of TRPM7 reverses these phenotypic changes, as does, unexpectedly, expression of a kinase-inactive mutant of TRPM7. Surprisingly, expression of the Mg²+ transporter SLC41A2 (solute carrier family 41 member 2) is also effective in restoring the change in cell morphology, disruption of the cytoskeleton and directional cell motility caused by depletion of the channel-kinase. The results of the present study uncover an essential role for Mg²+ in the control of TRPM7 over the cytoskeleton and its ability to regulate polarized cell movements.

Decreased Mg(2+) concentration has been implicated in altered vascular reactivity, endothelial dysfunction and structural remodeling, processes important in vascular changes and target organ damage associated with hypertension. Unlike our knowledge of other major cations, mechanisms regulating cellular Mg(2+) handling are poorly understood. Until recently little was known about protein transporters controlling transmembrane Mg(2+) influx. However, new research has uncovered a number of genes and proteins identified as transmembrane Mg(2+) transporters, particularly transient receptor potential melastatin (TRPM) cation channels, TRPM6 and TRPM7. Whereas TRPM6 is found primarily in epithelial cells, TRPM7 is ubiquitously expressed. Vascular TRPM7 has been implicated as a signaling kinase involved in vascular smooth muscle cell growth, apoptosis, adhesion, contraction, cytoskeletal organization and migration, and is modulated by vasoactive agents, pressure, stretch and osmotic changes. Emerging evidence suggests that vascular TRPM7 function might be altered in hypertension. The present review discusses the importance of Mg(2+) in vascular biology in hypertension and focuses on transport systems, mainly TRPM7, that might play a role in the control of vascular Mg(2+) homeostasis. Elucidation of the relationship between the complex systems responsible for regulation of Mg(2+) homeostasis, the role of TRPM7 in vascular signaling, and the cardiovascular impact will be important for understanding the clinical implications of hypomagnesemia in cardiovascular disease.

Context: ATP-sensitive potassium (KATP) channels regulate insulin secretion by coupling glucose metabolism to β-cell membrane potential. Gain-of-function mutations in the sulfonylurea receptor 1 (SUR1) or Kir6.2 channel subunit underlie neonatal diabetes., Objective: The objective of the study was to determine the mechanisms by which two SUR1 mutations, E208K and V324M, associated with transient neonatal diabetes affect KATP channel function., Design: E208K or V324M mutant SUR1 was coexpressed with Kir6.2 in COS cells, and expression and gating properties of the resulting channels were assessed biochemically and electrophysiologically., Results: Both E208K and V324M augment channel response to MgADP stimulation without altering sensitivity to ATP4- or sulfonylureas. Surprisingly, whereas E208K causes only a small increase in MgADP response consistent with the mild transient diabetes phenotype, V324M causes a severe activating gating defect. Unlike E208K, V324M also impairs channel expression at the cell surface, which is expected to dampen its functional impact on β-cells. When either mutation was combined with a mutation in the second nucleotide binding domain of SUR1 previously shown to abolish Mg-nucleotide response, the activating effect of E208K and V324M was also abolished. Moreover, combination of E208K and V324M results in channels with Mg-nucleotide sensitivity greater than that seen in individual mutations alone., Conclusion: The results demonstrate that E208K and V324M, located in distinct domains of SUR1, enhance transduction of Mg-nucleotide stimulation from the SUR1 nucleotide binding folds to Kir6.2. Furthermore, they suggest that diabetes severity is determined by interplay between effects of a mutation on channel expression and channel gating.

A search of the Streptomyces avermitilis genome reveals that its closest homologs are several O-methyltransferases. Among them, one gene (viz., saomt5) was cloned into the pET-15b expression vector by polymerase chain reaction using sequence-specific oligonucleotide primers. Biochemical characterization with the recombinant protein showed that SaOMT5 was S-adenosyl-L-methionine-dependent Omethyltransferase. Several compounds were tested as substrates of SaOMT5. As a result, SaOMT5 catalyzed Omethylation of flavonoids such as 6,7-dihydroxyflavone, 2',3'-dihydroxyflavone, 3',4'-dihydroxyflavone, quercetin, and 7,8-dihydroxyflavone, and phenolic compounds such as caffeic acid and caffeoyl Co-A. These reaction products were analyzed by TLC, HPLC, LC/MS, and NMR spectroscopy. In addition, SaOMT5 could convert phenolic compounds containing ortho-dihydroxy groups into Omethylated compounds, and 6,7-dihydroxyflavone was known to be the best substrate. SaOMT5 converted 6,7- dihydroxyflavone into 6-hydroxy-7-methoxyflavone and 7-hydroxy-6-methoxyflavone, and caffeic acid into ferulic acid and isoferulic acid, respectively. Moreover, SaOMT5 turned out to be a Mg2+-dependent OMT, and the effect of Mg2+ ion on its activity was five times greater than those of Ca2+, Fe2+, and Cu2+ ions, EDTA, and metal-free medium.

About 60% of adults in the United States do not consume the estimated average requirement for magnesium, but widespread pathological conditions attributed to magnesium deficiency have not been reported. Nevertheless, low magnesium status has been associated with numerous pathological conditions characterized as having a chronic inflammatory stress component. In humans, deficient magnesium intakes are mostly marginal to moderate (approximately 50% to <100% of the recommended dietary allowance). Animal experiments indicate that signs of marginal-to-moderate magnesium deficiency can be compensated or exacerbated by other factors influencing inflammatory and oxidative stress; recent studies suggest a similar happening in humans. This suggestion may have significance in obesity, which is characterized as having a chronic low-grade inflammation component and an increased incidence of a low magnesium status. Marginal-to-moderate magnesium deficiency through exacerbating chronic inflammatory stress may be contributing significantly to the occurrence of chronic diseases such as atherosclerosis, hypertension, osteoporosis, diabetes mellitus, and cancer.

Magnesium is related to a number of biological enzymatic reactions such as catalytic role for the reaction of kinases in ATP production. On the other hand, magnesium is one of the essential minerals for bone formation. In the magnesium-deficient rats, apparent bone loss caused by increase in bone resorption and decrease in bone formation was observed. Although, epidemiological studies suggest that magnesium deficiency is one of the risk factor for osteoporosis, a relationship between magnesium intake and bone mineral density is not clear. This may be due to the differences in the population, decrease in sex hormone secretion, and the possibility that magnesium-deficiency is also accompanied with another nutrient insufficiency, e.g., calcium.

Objective: To study the changes of glucocorticoid receptor (GR) expression in embryonic rat cortical neurons exposed to transient Mg(2+)-free treatment., Methods: Six days after rat cortical neuronal cultures, two groups were created based on the medium to which were transiently exposed. The control group was exposed to a physiological solution (PS), and the Mg(2+)-free group was exposed to the same medium as the control group except for the removal of magnesium. The expression of GR mRNA and protein was determined by real-time PCR and immunocytochemistry staining 1, 7 and 12 days after transient Mg(2+)-free treatment., Results: Compared to the control group, the Mg(2+)-free group displayed the significantly less accumulated optical density (AOD) of GR immunoreactivity 12 days after transient Mg(2+)-free treatment (p<0.05). On the contrary, GR mRNA expression increased significantly 1 and 7 days after transient Mg(2+)-free treatment in the Mg(2+)-free group (p<0.05)., Conclusions: GR expression is modified following Mg-free-induced injury in cultured developing neurons in rats.

The N-methyl-d-aspartate receptor (NMDAR) channel is one of the major excitatory amino acid receptors in the mammalian brain. Since external Mg(2+) blocks the channel in an apparently voltage-dependent fashion, this ligand-gated channel displays intriguing voltage-dependent control of Na(+) and Ca(2+) permeability and thus plays an important role in synaptic physiology. We found that the essential features of Mg(2+) block could not be solely envisaged by binding of a charged blocker in the membrane electric field. Instead, the blocking effect of Mg(2+) is critically regulated by, and quantitatively correlated with, the relative tendency of outward and inward ionic fluxes. The 'intrinsic' affinity of Mg(2+) to the binding sites, however, is low (in the millimolar range) in the absence of net ionic flow at 0 mV. Besides, extracellular and intracellular Mg(2+) blocks the channel at distinct sites of electrical distances 0.7 and 0.95 from the outside, respectively. The two sites are separated by a high energy barrier for the movement of Mg(2+) (but not Na(+) or the other ions), and functionally speaking, each could accommodate 1.1 and 0.8 coexisting permeating ions, respectively. Mg(2+) block of the ionic flow thus is greatly facilitated by the flux-coupling effect or the ionic flow (the preponderant direction of permeant ion movement) per se, as if the poorly permeable Mg(2+) is 'pushed' against a high energy barrier by the otherwise permeating ions. Extracellular and intracellular Mg(2+) block then is in essence 'use dependent', more strongly inhibiting both Na(+) and Ca(2+) fluxes with stronger tendencies of influx and efflux, respectively. In conclusion, although permeant ions themselves could compete with Mg(2+), the flow or the tendency of movement of the permeant ions may actually enhance rather than interfere with Mg(2+) block, making the unique current-voltage relationship of NMDAR and the molecular basis of many important neurobiological phenomena.

Elevation of cerebral Mg2+ with a novel orally delivered ionophore, magnesium threonate, enhances cognition in young and old rats over a 12-24 day treatment interval, as outlined in a paper by Slutsky et al. in this issue of Neuron. Despite both Mg2+ and Zn2+ blocking the NMDA receptor channel, sustained extracellular Mg2+ elevation mimics sustained synaptic Zn2+ concentrations by increasing hippocampal NR2B expression and bouton density., (Copyright 2010 Elsevier Inc. All rights reserved.)

Learning and memory are fundamental brain functions affected by dietary and environmental factors. Here, we show that increasing brain magnesium using a newly developed magnesium compound (magnesium-L-threonate, MgT) leads to the enhancement of learning abilities, working memory, and short- and long-term memory in rats. The pattern completion ability was also improved in aged rats. MgT-treated rats had higher density of synaptophysin-/synaptobrevin-positive puncta in DG and CA1 subregions of hippocampus that were correlated with memory improvement. Functionally, magnesium increased the number of functional presynaptic release sites, while it reduced their release probability. The resultant synaptic reconfiguration enabled selective enhancement of synaptic transmission for burst inputs. Coupled with concurrent upregulation of NR2B-containing NMDA receptors and its downstream signaling, synaptic plasticity induced by correlated inputs was enhanced. Our findings suggest that an increase in brain magnesium enhances both short-term synaptic facilitation and long-term potentiation and improves learning and memory functions., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background and Objectives: Magnesium is predominantly an intracellular ion. Its blocking effects on NMDA receptors are responsible for the analgesic and sedative characteristics of this ion. The objective of this study was to review the physiology, pharmacology, and decreased plasma levels of magnesium, as well as its applications in obstetrics and anesthesia., Contents: Magnesium is an intracellular cation with multiple functions: it is a cofactor for enzymes of the glucose metabolism and those that participate in the degradation of nucleic acids, proteins, and fatty acids; it regulates the movements of transmembrane ions; and it intervenes in the activity of several enzymes. Critical patients have a tendency to develop hypomagnesemia, and the treatment consists in correcting the cause, whenever possible, and replacement of magnesium. A reduction in the minimum alveolar concentration (MAC) of inhalational agents in animals and the use of opioids in humans under anesthesia has been demonstrated., Conclusions: Magnesium sulfate has been used in obstetrics with good results, inhibiting premature labor and in the treatment of eclampsia-associated seizures. It is potentially analgesic and sedative, and could be used as adjuvant during general anesthesia, attenuating the blood pressure response to tracheal intubation and decreasing the need of anesthetics.

Traumatic brain injury (TBI) confers a major burden to Western society and effective treatments are urgently required to improve the long-term deficits that inflict TBI survivors. Depletion of intracellular Mg(2+) is a well-known phenomenon occurring after TBI and is associated with poor neurological outcome. However, despite success in pre-clinical experimental studies, therapies utilizing Mg(2+) have not always proven to be clinically effective. Recent evidence implicates members of the transient receptor potential melastatin (TRPM) channel family in processes leading to neuronal cell death following ischemic injury, however, the exact mechanism by which this occurs is not completely understood. Specifically, TRPM7 and TRPM6 are two channels that have been identified as potentially playing a role in regulating Mg(2+) homeostasis, although whether this role in magnesium regulation and neuronal injury is significant is controversial. The purpose of this review is to explore the relationship between TRPM family members and Mg(2+) homeostasis, including their potential involvement in secondary injury processes leading to cell death following TBI.

Aging is very often associated with magnesium (Mg) deficit. Total plasma magnesium concentrations are remarkably constant in healthy subjects throughout life, while total body Mg and Mg in the intracellular compartment tend to decrease with age. Dietary Mg deficiencies are common in the elderly population. Other frequent causes of Mg deficits in the elderly include reduced Mg intestinal absorption, reduced Mg bone stores, and excess urinary loss. Secondary Mg deficit in aging may result from different conditions and diseases often observed in the elderly (i.e. insulin resistance and/or type 2 diabetes mellitus) and drugs (i.e. use of hypermagnesuric diuretics). Chronic Mg deficits have been linked to an increased risk of numerous preclinical and clinical outcomes, mostly observed in the elderly population, including hypertension, stroke, atherosclerosis, ischemic heart disease, cardiac arrhythmias, glucose intolerance, insulin resistance, type 2 diabetes mellitus, endothelial dysfunction, vascular remodeling, alterations in lipid metabolism, platelet aggregation/thrombosis, inflammation, oxidative stress, cardiovascular mortality, asthma, chronic fatigue, as well as depression and other neuropsychiatric disorders. Both aging and Mg deficiency have been associated to excessive production of oxygen-derived free radicals and low-grade inflammation. Chronic inflammation and oxidative stress are also present in several age-related diseases, such as many vascular and metabolic conditions, as well as frailty, muscle loss and sarcopenia, and altered immune responses, among others. Mg deficit associated to aging may be at least one of the pathophysiological links that may help to explain the interactions between inflammation and oxidative stress with the aging process and many age-related diseases.

Magnesium ion (Mg(2+)) and calcium ion (Ca(2+)) control a diverse and important range of cellular processes, such as gene transcription, cell proliferation, neoplastic transformation, immune response and therapeutic treatment. Their characteristic biologic antagonism makes it important to treat the most important aspects of that competitive behavior together. This synopsis aims to be a useful means of promoting further research on the relationship between both cations and human health affected by environmental conditions.

Purpose: To review randomized control clinical trial (RCT) literature and prospective studies for the safety and efficacy of magnesium supplements in patients with coronary heart disease (CHD) or with CHD risk., Data Sources: Databases were searched using the keywords: magnesium, heart disease, endothelium, prevention, treatment, therapy, level, and supplement., Conclusions: There were no reports of adverse effects from magnesium supplementation in any of the studies. Subjects reporting lower dietary magnesium intake had significantly lower serum magnesium concentrations than those reporting higher dietary magnesium intake and, in some cases, had a significantly higher frequency of supraventricular beats. There was a modest relationship between dietary magnesium intake and a reduced risk of CHD in male subjects; however, there was no noted decrease in the development of CHD disease in women who had high magnesium intake., Implications for Practice: Magnesium is vital for many functions in the body and magnesium supplementation is safe. There is a possible association between a modestly lower risk of CHD in men and increased magnesium intake; therefore, it is reasonable to encourage diets high in magnesium as a potential means to lower the risk of CHD.

The MgtE family of Mg(2+) transporters is ubiquitously distributed in all phylogenetic domains. Recent crystal structures of the full-length MgtE and of its cytosolic domain in the presence and absence of Mg(2+) suggested a Mg(2+)-homeostasis mechanism, in which the MgtE cytosolic domain acts as a 'Mg(2+) sensor' to regulate the gating of the ion-conducting pore in response to the intracellular Mg(2+) concentration. However, complementary functional analyses to confirm the proposed model have been lacking. Moreover, the limited resolution of the full-length structure precluded an unambiguous characterization of these regulatory divalent-cation-binding sites. Here, we showed that MgtE is a highly Mg(2+)-selective channel gated by Mg(2+) and elucidated the Mg(2+)-dependent gating mechanism of MgtE, using X-ray crystallographic, genetic, biochemical, and electrophysiological analyses. These structural and functional results have clarified the control of Mg(2+) homeostasis through cooperative Mg(2+) binding to the MgtE cytosolic domain.

Magnesium deficiency and hypomagnesemia remain quite prevalent, particularly in patients in intensive care units, and may have important clinical consequences. Magnesium should be measured directly in clinical circumstances in which a risk for magnesium deficiency exists and appropriately corrected when found. This commentary reviews the current knowledge of magnesium homeostasis and the risk factors and clinical consequences of magnesium deficiency and outlines approaches to therapy.

The role of divalent cations (i.e. Ca(2+) and Mg(2+)) in the deposition kinetics of the bacteriophage MS2 onto flat bare silica surfaces and Suwannee River Natural Organic Matter (SRNOM)-coated silica surfaces was investigated using a Quartz Crystal Microbalance (QCM) coupled with a radial stagnation point flow (RSPF) system. Experimental results demonstrated that attachment efficiencies of MS2 onto the SRNOM surface were seven to seventeen times higher in the presence of Ca(2+) than in the presence of Mg(2+). A similar trend was observed for the adsorption of polyglutamic acid, which is one of the carboxylate-containing amino acid residues found on the surface of MS2 capsids present on SRNOM-coated surfaces. The difference in attachment rates in a solution containing either Ca(2+) or Mg(2+) can be explained by a stronger tendency of Ca(2+) compared to Mg(2+) to form cation bridges by binding to carboxylate groups of both the SRNOM and the MS2 capsids. Moreover, higher attachment efficiencies of MS2 onto the SRNOM-coated silica surfaces compared to those on bare silica surfaces in the presence of either Ca(2+) or Mg(2+) at concentrations higher than 0.3 mM emphasized the important role of SRNOM carboxylate groups. Experimental data also showed reduced attachment efficiency of MS2 to SRNOM-coated surfaces in solution containing 1 mg/L SRNOM.

Deficiency of minerals causes functional abnormality of enzymes, frequently resulting in metabolic disturbance. We investigated possible relationship between minerals and metabolic syndrome by analysis of hair tissue minerals. We selected 848 subjects older than 20 years of age at Ajou University Hospital from May 2004 to February 2007. We excluded the subjects who had cancers, steroid and thyroid medication, and incomplete record from the study. Finally, 343 subjects were eligible. We performed cross-sectional analysis for the relationship between minerals and metabolic syndrome. The contents of calcium, magnesium, and copper in the metabolic syndrome group were significantly lower than those of the normal group, whereas the amounts of sodium, potassium, and mercury in the metabolic syndrome group were significantly higher than those of the normal group. By dividing the subjects into quartile with the level of calcium, magnesium, and mercury concentrations, we carried out logistic regression analysis to study the subjects and found that the subjects in the third quartile of calcium and magnesium concentrations had significantly lower odds ratio (OR) of the metabolic syndrome compared with that of the lowest quartile group [OR = 0.30, confidence interval (CI) = 0.10-0.89; OR = 0.189, CI = 0.063-0.566] and that the subjects in the highest mercury quartile had significantly higher OR of the metabolic syndrome compared with that of the lowest mercury quartile group (OR = 7.35, CI = 1.73-31.1). As part of the metabolic syndrome, the optimal calcium and magnesium concentrations in hair tissue may reflect decreased risk of metabolic syndrome, whereas high mercury concentration in hair tissue may indicate increased risk of metabolic syndrome.

N-methyl-D-aspartate receptors (NMDARs) are ion channels gated by glutamate, the major excitatory neurotransmitter in the mammalian central nervous system (CNS). They are widespread in the CNS and are involved in numerous physiological and pathological processes including synaptic plasticity, chronic pain and psychosis. Aberrant NMDAR activity also plays an important role in the neuronal loss associated with ischaemic insults and major degenerative disorders including Parkinson's and Alzheimer's disease. Agents that target and alter NMDAR function may, thus, have therapeutic benefit. Interestingly, NMDARs are endowed with multiple extracellular regulatory sites that recognize ions or small molecule ligands, some of which are likely to regulate receptor function in vivo. These allosteric sites, which differ from agonist-binding and channel-permeation sites, provide means to modulate, either positively or negatively, NMDAR activity. The present review focuses on allosteric modulation of NMDARs containing the NR2B subunit. Indeed, the NR2B subunit confers a particularly rich pharmacology with distinct recognition sites for exogenous and endogenous allosteric ligands. Moreover, NR2B-containing receptors, compared with other NMDAR subtypes, appear to contribute preferentially to pathological processes linked to overexcitation of glutamatergic pathways. The actions of extracellular H+, Mg2+, Zn2+, of polyamines and neurosteroids, and of the synthetic compounds ifenprodil and derivatives ('prodils') are presented. Particular emphasis is put upon the structural determinants and molecular mechanisms that underlie the effects exerted by these agents. A better understanding of how NR2B-containing NMDARs (and NMDARs in general) operate and how they can be modulated should help define new strategies to counteract the deleterious effects of dysregulated NMDAR activity.

Magnesium is an essential mineral for optimal metabolic function. Research has shown that the mineral content of magnesium in food sources is declining, and that magnesium depletion has been detected in persons with some chronic diseases. This has led to an increased awareness of proper magnesium intake and its potential therapeutic role in a number of medical conditions. Studies have shown the effectiveness of magnesium in eclampsia and preeclampsia, arrhythmia, severe asthma, and migraine. Other areas that have shown promising results include lowering the risk of metabolic syndrome, improving glucose and insulin metabolism, relieving symptoms of dysmenorrhea, and alleviating leg cramps in women who are pregnant. The use of magnesium for constipation and dyspepsia are accepted as standard care despite limited evidence. Although it is safe in selected patients at appropriate dosages, magnesium may cause adverse effects or death at high dosages. Because magnesium is excreted renally, it should be used with caution in patients with kidney disease. Food sources of magnesium include green leafy vegetables, nuts, legumes, and whole grains.

The adverse role played by inflammation in the etiology of humankind's most prevalent chronic diseases compels researchers to work diligently to explore its biologic basis. Recent research supports the concept of an important relationship between dietary factors and inflammation, and in particular the role of magnesium deficiency, however, the specifics of this association are not completely understood. Recent findings from epidemiologic studies support that magnesium intake is inversely associated with C-reactive protein concentration, an important marker of inflammation strongly associated with cardiovascular disease risk. Animal studies have provided many mechanistic possibilities to explain the link between magnesium and inflammation. Further research is needed to understand more completely the role of magnesium in inflammation.

Receptor subtypes involved in the 5-hydroxytryptamine (5-HT)-induced depression of synaptic transmission in neonatal rat spinal cords in vitro were evaluated in the absence or presence of Mg(2+) in the medium. Stimulation of a dorsal root evoked monosynaptic reflex potential (MSP) and polysynaptic reflex potential (PSP) in the segmental ventral root in Mg(2+)-free medium where the voltage-dependent blockade of NMDA receptors is absent. The 5-HT (0.3-50 microM) in the Mg(2+)-free medium depressed the MSP and PSP in a concentration-dependent manner. At 30 microM of 5-HT, the depression was 57% and 95% for MSP and PSP, respectively, and no further depression was seen at 50 microM. The 5-HT-induced depression of the reflexes in the Mg(2+)-free medium was blocked by ondansetron (5-HT(3) receptor antagonist), but not by spiperone (5-HT(2A/2C) antagonist). In the Mg(2+)-free medium, phenylbiguanide (5-HT(3) agonist) also depressed the MSP and PSP in a concentration-dependent manner and was blocked by ondansetron. Addition of Mg(2+) (1.3 mM) to the medium abolished the PSP and decreased the MSP by 30%. In the presence of Mg(2+), 5-HT (1-50 microM) also depressed the MSP in a concentration-dependent manner. At 10 microM of 5-HT, there was approximately 20% depression and at 50 microM the depression was 100%. The 5-HT-induced depression of MSP in the Mg(2+)-containing medium was antagonized by spiperone (p < 0.05, two-way ANOVA), but not by ondansetron. The results indicate that the 5-HT-induced depression of MSP involves 5-HT(3) receptors in the Mg(2+)-free medium and 5-HT(2A/2C) in the presence of Mg(2+) when NMDA receptors are in the closed state.

Competitive divalent (magnesium and calcium) or monovalent (potassium, lithium and sodium) ion exchange and its influence on a membrane potential formation was studied at biological ligands (BL) such as adenosine triphosphate (ATP), asparagine (Asn) and glutamine (Gln) sites. The sites are dispersed electrochemically in membranes made of the conducting polymers (CPs)--poly(N-methylpyrrole) (PMPy) and poly(pyrrole) (PPy). The membranes are made sensitive to calcium and magnesium or to potassium, sodium and lithium by optimized electrodeposition and soaking procedures supported by the study of membrane topography and morphology. Distinctively different electrochemical responses, i.e. electrical potential transients or currents, are observed in the case of "antagonistic" calcium and magnesium or potassium and sodium/lithium ion pairs. Dissimilarity in the responses is ascribed to a difference between on site vs. bulk concentrations of ions, and is dictated by different transport properties of the ions, as shown by using the Nernst-Planck-Poisson (NPP) model and the diffusion-layer model (DLM). The method described allows inspecting potential-dependent competitive ion-exchange processes at the biologically active sites. It is suggested that this approach could be used as an auxiliary tool in study of potential dependent block in realistic membrane channels, such as Mg block in the N-methyl D-aspartate receptor channel (NMDA).

Recent polymorphism analyses of Mycobacterium tuberculosis strains have identified missense mutations unique to the W-Beijing lineage in genes belonging to the Nudix hydrolase superfamily. This study investigates the structure and function of one of these Nudix hydrolases, MutT2, and examines the effect that the W-Beijing mutation (G58R) has on enzyme characteristics. MutT2 has a preference for cytidine triphosphates, and although the G58R mutation does not alter nucleotide specificity, it reduces the protein's affinity for divalent cations. The K(D) of free Mg(2+) is 79-fold higher for the G58R mutant (3.30 +/- 0.19 mM) compared with that for the wild-type (41.7 +/- 1.4 microM). Circular dichroism and nuclear magnetic resonance spectroscopy measurements show that while the mutation does not perturb the overall structure of the protein, protein stability is significantly compromised by the presence of the arginine with DeltaG (H(2)O), the free-energy of unfolding, being reduced by 2.48 kcal mol(-1) in the G58R mutant. Homology modeling of MutT2 shows that Gly-58 is in close proximity (10.8 A) to the Mg(2+) binding site formed by the highly conserved Nudix box residues and hydrogen bonds with Ala-54 in the preceding alpha-helix. This may explain the increased divalent cation requirement and decreased stability observed when an arginine is substituted for glycine at this position. A role for MutT2 in the regulation of cytidine-triphosphates available for nucleotide-dependent reactions is postulated, and the impact that the G58R mutation may have on these reactions is discussed.

A bacterial strain isolated from the oral cavity of a healthy dog revealed an unusual colony formation in nebular appearance on agar plates. The isolated bacterial strain was Gram-positive, spore-forming rod with peritrichous flagella, and grown under aerobic conditions, but unable to grow at 45 degrees C. The strain was tentatively classified as Paenibacillus alvei according to the biochemical properties and the 16S rRNA gene sequence. The isolate exhibits collective locomotion on solid agar plates. The bacterial motility was inhibited with EDTA and was restored by adding magnesium. We concluded that magnesium ion is essential for collective locomotion of P. alvei. This suggests that EDTA is useful for inhibition of biofilm formation.

The physiology of calcium and the other minerals involved in its metabolism is complex and intimately tied in with the physiology of bone. Five principal humoral factors are involved in maintaining plasma levels of calcium, magnesium and phosphate and coordinating the balance between these and their content in bone. The transmembrane transport of these elements is dependent on a series of complex mechanisms that are controlled by these hormones. The plasma concentration of calcium is initially sensed by a calcium-sensing receptor which then sets up a cascade of events that initially determines parathyroid hormone secretion and eventually results in a specific action within the target organs, mainly bone and kidney. This chapter describes the physiology of these humoral factors and relates them to the pathological processes that give rise to disorders of calcium and bone metabolism. It details the stages in the calcium cascade and describes the effects on the various target organs. The pathology of disorders of bone and calcium metabolism is described in detail in the relevant chapters., (Copyright (c) 2009 S. Karger AG, Basel.)

Ligand-gated ion channels are activated by agonist binding, but may also be modulated by membrane voltage. N-Methyl-d-aspartate receptors (NMDARs) exhibit especially strong voltage dependence due to channel block by external Mg(2+) (Mg(o)(2+)). Here we demonstrate that activity of NMDARs composed of NR1 and NR2B subunits (NR1/2B receptors) is enhanced by depolarization even in 0 Mg(o)(2+), causing slow current relaxations in response to rapid voltage changes. We present a kinetic model of receptor activation that incorporates voltage-dependent gating-associated NR2B subunit conformational changes. The model accurately reproduces current relaxations during depolarizations and subsequent repolarizations in 0 Mg(o)(2+). Model simulations in physiological Mg(o)(2+) concentrations show that voltage-dependent receptor gating also underlies the slow component of Mg(o)(2+) unblock, a phenomenon that previously was shown to influence Mg(o)(2+) unblock kinetics during dendritic spikes. We propose that voltage-dependent gating of NR1/2B receptors confers enhanced voltage and time dependence on NMDAR-mediated signalling.

The HIV replication cycle passes through a stage of integrating proviral DNA into the cell's DNA. In this process, the viral enzyme, integrase, catalyses two reactions. The first reaction, which seems to occur in the cytoplasm, involves 3'-end processing, in which two nucleotides are removed from the 3' ends of the viral DNA by integrase. The second reaction, which occurs in the nucleus, involves the strand transfer reaction, catalyzed by integrase, in which the recessed 3' ends of the viral DNA are joined to the protruding 5' ends in the target DNA. Although this activity has not yet been completely defined and the structure of the active form of integrase, probably a tetramer, has not been resolved, drugs of the diketoacid (DKA) family have been found. These drugs are highly potent inhibitors of the second phase, the strand transfer reaction. Through a series of optimizations, a highly effective molecule for clinical use, raltegravir, has been achieved. The present article provides a summary of basic knowledge on integrase, as well as the activity and the modes of inhibition of this enzyme. Also discussed is the reduced, but nevertheless real, development of resistance to raltegravir, requiring second-generation integrase inhibitors to be designed.

Polyunsaturated fatty acids (PUFAs) have beneficial effects on epileptic seizures and cardiac arrhythmia. We report that omega-3 and omega-6 all-cis-PUFAs affected the voltage dependence of the Shaker K channel by shifting the conductance versus voltage and the gating charge versus voltage curves in negative direction along the voltage axis. Uncharged methyl esters of the PUFAs did not affect the voltage dependence, whereas changes of pH and charge mutations on the channel surface affected the size of the shifts. This suggests an electrostatic effect on the channel's voltage sensors. Monounsaturated and saturated fatty acids, as well as trans-PUFAs did not affect the voltage dependence. This suggests that fatty acid tails with two or more cis double bonds are required to place the negative carboxylate charge of the PUFA in a position to affect the channel's voltage dependence. We propose that charged lipophilic compounds could play a role in regulating neuronal excitability by electrostatically affecting the channel's voltage sensor. We believe this provides a new approach for pharmacological treatment that is voltage sensor pharmacology.

Calcium and magnesium are essential for survival but it is unknown how animals detect and consume enough of these minerals to meet their needs. To investigate this, we exploited the PWK/PhJ (PWK) strain of mice, which, in contrast to the C57BL/6J (B6) and other inbred strains, displays strong preferences for calcium solutions. We found that the PWK strain also has strong preferences for MgCl2 and saccharin solutions but not representative salty, sour, bitter, or umami taste compounds. A genome scan of B6 x PWK F2 mice linked a component of the strain difference in calcium and magnesium preference to distal chromosome 4. The taste receptor gene, Tas1r3, was implicated by studies with 129.B6ByJ-Tas1r3 congenic and Tas1r3 knockout mice. Most notably, calcium and magnesium solutions that were avoided by wild-type B6 mice were preferred (relative to water) by B6 mice null for the Tas1r3 gene. Oral calcium elicited less electrophysiological activity in the chorda tympani nerve of Tas1r3 knockout than wild-type mice. Comparison of the sequence of Tas1r3 with calcium and saccharin preferences in inbred mouse strains found 1) an inverse correlation between calcium and saccharin preference scores across primarily domesticus strains, which was associated with an I60T substitution in T1R3, and 2) a V689A substitution in T1R3 that was unique to the PWK strain and thus may be responsible for its strong calcium and magnesium preference. Our results imply that, in addition to its established roles in the detection of sweet and umami compounds, T1R3 functions as a gustatory calcium-magnesium receptor.

An abundant oxidative lesion, 8-oxo-7,8-dihydroguanine (8-oxoG), often directs the misincorporation of dAMP during replication. To prevent mutations, cells possess an enzymatic system for the removal of 8-oxoG. A key element of this system is 8-oxoguanine-DNA glycosylase (Fpg in bacteria, OGG1 in eukaryotes), which must excise 8-oxoG from 8-oxoG:C pairs but not from 8-oxoG:A. We investigated the influence of various factors, including ionic strength, the presence of Mg(2+) and organic anions, polyamides, crowding agents and two small heterocyclic compounds (biotin and caffeine) on the activity and opposite-base specificity of Escherichia coli Fpg and human OGG1. The activity of both enzymes towards 8-oxoG:A decreased sharply with increasing salt and Mg(2+) concentration, whereas the activity on 8-oxoG:C was much more stable, resulting in higher opposite-base specificity when salt and Mg(2+) were at near-physiological concentrations. This tendency was observed with both Cl(-) and glutamate as the major anions in the reaction mixture. Kinetic and binding parameters for the processing of 8-oxoG:C and 8-oxoG:A by Fpg and OGG1 were determined under several different conditions. Polyamines, crowding agents, biotin and caffeine affected the activity and specificity of Fpg or OGG1 only marginally. We conclude that, in the intracellular environment, the specificity of Fpg and OGG1 for 8-oxoG:C versus 8-oxoG:A is mostly due to high ionic strength and Mg(2+).

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are activated by membrane hyperpolarization that creates time-dependent, inward rectifying currents, gated by the movement of the intrinsic voltage sensor S4. However, inward rectification of the HCN currents is not only observed in the time-dependent HCN currents, but also in the instantaneous HCN tail currents. Inward rectification can also be seen in mutant HCN channels that have mainly time-independent currents (5). In the present study, we show that intracellular Mg(2+) functions as a voltage-dependent blocker of HCN channels, acting to reduce the outward currents. The affinity of HCN channels for Mg(2+) is in the physiological range, with Mg(2+) binding with an IC(50) of 0.53 mM in HCN2 channels and 0.82 mM in HCN1 channels at +50 mV. The effective electrical distance for the Mg(2+) binding site was found to be 0.19 for HCN1 channels, suggesting that the binding site is in the pore. Removing a cysteine in the selectivity filter of HCN1 channels reduced the affinity for Mg(2+), suggesting that this residue forms part of the binding site deep within the pore. Our results suggest that Mg(2+) acts as a voltage-dependent pore blocker and, therefore, reduces outward currents through HCN channels. The pore-blocking action of Mg(2+) may play an important physiological role, especially for the slowly gating HCN2 and HCN4 channels. Mg(2+) could potentially block outward hyperpolarizing HCN currents at the plateau of action potentials, thus preventing a premature termination of the action potential.

Ligand binding to transport sites constitutes the initial step in the catalytic cycle of transport ATPases. Here, we consider the well characterized Ca2+ ATPase of sarcoplasmic reticulum (SERCA) and describe a series of Ca2+ binding isotherms obtained by equilibrium measurements in the presence of various H+ and Mg2+ concentrations. We subject the isotherms to statistical mechanics analysis, using a model based on a minimal number of mechanistic steps. The analysis allows satisfactory fits and yields information on occupancy of the specific Ca2+ sites under various conditions. It also provides a fundamental method for analysis of binding specificity to transport sites under equilibrium conditions that lead to tightly coupled catalytic activation.

Despite advances in the prevention and treatment of hypertension over the past decade, hypertension remains an important public health challenge. Recent efforts to reduce the prevalence of hypertension have focused on nonpharmacologic means, specifically diet. An increased intake of minerals such as potassium, magnesium, and calcium by dietary means has been shown in some but not all studies to reduce blood pressure in patients with hypertension. This review will discuss the roles of potassium, magnesium, and calcium in the prevention and treatment of essential hypertension with specific emphasis on clinical trial evidence, mechanism of action, and recommendations for dietary intake of these minerals. A high intake of these minerals through increased consumption of fruits and vegetables may improve blood pressure levels and reduce coronary heart disease and stroke.

Objective: We investigated the long-term effects of maternal/postnatal magnesium (Mg) restriction on adiposity, glucose tolerance, and insulin secretion in the offspring and the probable biochemical mechanisms associated with them., Methods and Procedures: Female weanling Wistar/NIN (WNIN) rats received a control diet or 70% Mg-restricted (MgR) diet for 9 weeks and mated with control males. A third of the restricted dams were shifted to control diet from parturition. Half of the pups born to the remaining restricted dams were weaned on to control diet, while the other half continued on MgR diet. Various parameters were determined in the offspring at 18 months of age., Results: The percentage of body fat increased, lean body mass (LBM) and fat free mass (FFM) decreased in restricted offspring and were irreversible by rehabilitation. While glucose tolerance and insulin resistance (IR) were comparable among groups, glucose-stimulated insulin secretion and basal glucose uptake by the diaphragm were significantly decreased in restricted offspring and not corrected by rehabilitation. Plasma leptin was lower, and tumor necrosis factor-alpha (TNF-alpha) was higher in restricted offspring, whereas expression of fatty acid synthase (FAS) and fatty acyl transport protein 1 (FATP 1) was higher in liver and adipose tissue. While changes in FAS and FATP 1 were not correctible by rehabilitation, those in leptin and TNF-alpha were corrected by rehabilitation from parturition but not from weaning. Tissue oxidative stress and antioxidant status were comparable among groups., Discussion: Results indicate that maternal and postnatal Mg status is important in the long-term programming of body adiposity and insulin secretion in rat offspring.