Potassium Homeostasis Research Articles

Inactivation of a New Potassium Channel Increases Rifampicin Resistance and Induces Collateral Sensitivity to Hydrophilic Antibiotics in Mycobacterium smegmatis

Rifampicin is a critical first-line antibiotic for treating mycobacterial infections such as tuberculosis, one of the most serious infectious diseases worldwide. Rifampicin resistance in mycobacteria is mainly caused by mutations in the rpoB gene; however, some rifampicin-resistant strains showed no rpoB mutations. Therefore, alternative mechanisms must explain this resistance in mycobacteria. In this work, a library of 11,000 Mycobacterium smegmatis mc2 155 insertion mutants was explored to search and characterize new rifampicin-resistance determinants. A transposon insertion in the MSMEG_1945 gene modified the growth rate, pH homeostasis and membrane potential in M. smegmatis, producing rifampicin resistance and collateral susceptibility to other antitubercular drugs such as isoniazid, ethionamide and aminoglycosides. Our data suggest that the M. smegmatis MSMEG_1945 protein is an ion channel, dubbed MchK, essential for maintaining the cellular ionic balance and membrane potential, modulating susceptibility to antimycobacterial agents. The functions of this new gene point once again to potassium homeostasis impairment as a proxy to resistance to rifampicin. This study increases the known repertoire of mycobacterial ion channels involved in drug susceptibility/resistance to antimycobacterial drugs and suggests novel intervention opportunities, highlighting ion channels as druggable pathways.

Pattern Recognition versus Pathogenesis: Electrolytes in a Patient with Adrenal Insufficiency.

Pattern Recognition versus Pathogenesis: Electrolytes in a Patient with Adrenal Insufficiency.

Real-world clinical burden and economic assessment associated with hyperkalaemia in a large integrated healthcare system: a retrospective analysis

BackgroundHyperkalaemia (HK) is a serious and potentially life-threatening condition. Both acute and chronic conditions may alter potassium homeostasis. Our aim is to describe HK incidence, clinical outcomes, and associated resource use within a large, integrated healthcare system.MethodsAdult patients seen at Intermountain Healthcare facilities with a serum potassium (sK) result between January 1, 2003 and December 31, 2018 were retrospectively studied. Descriptive assessment of a population with detected HK, defined by any sK > 5.0 mmol/L and HK frequency and severity to associated resource use and characteristics of HK predictors were made. Multivariable Cox hazard regression was used to evaluate HK to outcomes.ResultsOf 1,208,815 patients included, 13% had HK. Compared to no-HK, HK patients were older (60 ± 18 vs 43 ± 18 years, P < 0.001), male (51% vs 41%, P < 0.001), and had greater disease burden (Charlson Comorbidity Index 3.5 ± 2.8 vs 1.7 ± 1.4, P < 0.001). At 3 years, more HK patients experienced major adverse cardiovascular events (MACEs) (19 vs 3%, P < 0.001), persisting post-adjustment (multivariable hazard ratio = 1.60, P < 0.001). They incurred higher costs for emergency department services ($552 ± 7,574 vs $207 ± 1,930, P < 0.001) and inpatient stays ($10,956 ± 93,026 vs $1,477 ± 21,423, P < 0.001). HyperK Risk Scores for the derivation and validation cohorts were: 44% low-risk, 45% moderate-risk, 11% high-risk. Strongest HK predictors were renal failure, dialysis, aldosterone blockers, diabetes, and smoking.ConclusionWithin this large system, HK was associated with a large clinical burden, affecting over 1 in 10 patients; HK was also associated with increased 3-year MACE risk and higher medical costs. Although risk worsened with more severe or persistently recurring HK, even mild or intermittent HK episodes were associated with significantly greater adverse clinical outcomes and medical costs. The HyperK Score predicted patients who may benefit from closer management to reduce HK risk and associated costs. It should be remembered that our assumptions are valid only for detected HK and not HK per se.

Inwardly Rectifying Potassium Channel Kir2.1 and its "Kir-ious" Regulation by Protein Trafficking and Roles in Development and Disease.

Potassium (K+) homeostasis is tightly regulated for optimal cell and organismal health. Failure to control potassium balance results in disease, including cardiac arrythmias and developmental disorders. A family of inwardly rectifying potassium (Kir) channels helps cells maintain K+ levels. Encoded by KCNJ genes, Kir channels are comprised of a tetramer of Kir subunits, each of which contains two-transmembrane domains. The assembled Kir channel generates an ion selectivity filter for K+ at the monomer interface, which allows for K+ transit. Kir channels are found in many cell types and influence K+ homeostasis across the organism, impacting muscle, nerve and immune function. Kir2.1 is one of the best studied family members with well-defined roles in regulating heart rhythm, muscle contraction and bone development. Due to their expansive roles, it is not surprising that Kir mutations lead to disease, including cardiomyopathies, and neurological and metabolic disorders. Kir malfunction is linked to developmental defects, including underdeveloped skeletal systems and cerebellar abnormalities. Mutations in Kir2.1 cause the periodic paralysis, cardiac arrythmia, and developmental deficits associated with Andersen-Tawil Syndrome. Here we review the roles of Kir family member Kir2.1 in maintaining K+ balance with a specific focus on our understanding of Kir2.1 channel trafficking and emerging roles in development and disease. We provide a synopsis of the vital work focused on understanding the trafficking of Kir2.1 and its role in development.

Estimating in vivo potassium distribution and fluxes with stable potassium isotopes.

Extracellular potassium (K+) homeostasis is achieved by a concerted effort of multiple organs and tissues. A limitation in studies of K+ homeostasis is inadequate techniques to quantify K+ fluxes into and out of organs and tissues in vivo. The goal of the present study was to test the feasibility of a novel approach to estimate K+ distribution and fluxes in vivo using stable K+ isotopes. 41K was infused as KCl into rats consuming control or K+-deficient chow (n = 4 each), 41K-to-39K ratios in plasma and red blood cells (RBCs) were measured by inductively coupled plasma mass spectrometry, and results were subjected to compartmental modeling. The plasma 41K/39K increased during 41K infusion and decreased upon infusion cessation, without altering plasma total K+ concentration ([K+], i.e., 41K + 39K). The time course of changes was analyzed with a two-compartmental model of K+ distribution and elimination. Model parameters, representing transport into and out of the intracellular pool and renal excretion, were identified in each rat, accurately predicting decreased renal K+ excretion in rats fed K+-deficient vs. control diet (P < 0.05). To estimate rate constants of K+ transport into and out of RBCs, 41K/39K were subjected to a simple model, indicating no effects of the K+-deficient diet. The findings support the feasibility of the novel stable isotope approach to quantify K+ fluxes in vivo and sets a foundation for experimental protocols using more complex models to identify heterogeneous intracellular K+ pools and to answer questions pertaining to K+ homeostatic mechanisms in vivo.

Low Salt Delivery Triggers Autocrine Release of Prostaglandin E2 From the Aldosterone-Sensitive Distal Nephron in Familial Hyperkalemic Hypertension Mice.

Aberrant activation of with-no-lysine kinase (WNK)-STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) kinase signaling in the distal convoluted tubule (DCT) causes unbridled activation of the thiazide-sensitive sodium chloride cotransporter (NCC), leading to familial hyperkalemic hypertension (FHHt) in humans. Studies in FHHt mice engineered to constitutively activate SPAK specifically in the DCT (CA-SPAK mice) revealed maladaptive remodeling of the aldosterone sensitive distal nephron (ASDN), characterized by decrease in the potassium excretory channel, renal outer medullary potassium (ROMK), and epithelial sodium channel (ENaC), that contributes to the hyperkalemia. The mechanisms by which NCC activation in DCT promotes remodeling of connecting tubule (CNT) are unknown, but paracrine communication and reduced salt delivery to the ASDN have been suspected. Here, we explore the involvement of prostaglandin E2 (PGE2). We found that PGE2 and the terminal PGE2 synthase, mPGES1, are increased in kidney cortex of CA-SPAK mice, compared to control or SPAK KO mice. Hydrochlorothiazide (HCTZ) reduced PGE2 to control levels, indicating increased PGE2 synthesis is dependent on increased NCC activity. Immunolocalization studies revealed mPGES1 is selectively increased in the CNT of CA-SPAK mice, implicating low salt-delivery to ASDN as the trigger. Salt titration studies in an in vitro ASDN cell model, mouse CCD cell (mCCD-CL1), confirmed PGE2 synthesis is activated by low salt, and revealed that response is paralleled by induction of mPGES1 gene expression. Finally, inhibition of the PGE2 receptor, EP1, in CA-SPAK mice partially restored potassium homeostasis as it partially rescued ROMK protein abundance, but not ENaC. Together, these data indicate low sodium delivery to the ASDN activates PGE2 synthesis and this inhibits ROMK through autocrine activation of the EP1 receptor. These findings provide new insights into the mechanism by which activation of sodium transport in the DCT causes remodeling of the ASDN.

Association of serum potassium level with early and late mortality in very elderly patients with acute kidney injury

BackgroundThe kidneys play a central role in serum potassium (K+) homeostasis, and their dysfunction leads to electrolyte disorders. We aimed to examine the relationship between different levels of K+ and mortality among very elderly patients with acute kidney injury (AKI). MethodsWe retrospectively enrolled very elderly patients (≥75 years) with AKI from the hospital information system of the Chinese PLA General Hospital from January 1, 2007 to December 31, 2018. All-cause mortality was examined according to six predefined K+ levels: <3.50 mmol/L, 3.50–3.79 mmol/L, 3.80–4.09 mmol/L, 4.10–4.79 mmol/L, 4.80–5.49 mmol/L, and ≥5.50 mmol/L. We estimated the risk of all-cause mortality using the multivariable adjusted Cox proportional hazard model with the normal K+ level at 3.50–3.79 mmol/L as a reference. ResultsIn total, 747 patients were deemed suitable for the final evaluation. The median age of the 747 participants was 88 (84–91) years. After 90 days, the mortality rates in the six strata were 28.3%, 21.9%, 30.1%, 35.4%, 45.2%, and 58.3%, respectively. In the multivariable adjusted analysis, patients with K+ levels of 4.10–4.79 mmol/L (hazard ratio [HR]: 1.638; 95% confidence interval [CI]: 1.016–2.642), 4.80–5.49 mmol/L (HR: 2.585; 95% CI: 1.524–4.384), and ≥5.50 mmol/L (HR: 2.587; 95% CI: 1.495–4.479) had an increased risk of all-cause mortality. After 1 year, the mortality rates in the six strata were 44.8%, 41.1%, 45.1%, 51.8%, 63.1%, and 76.3%, respectively. In the multivariable adjusted analysis, patients with K+ levels of 4.10–4.79 mmol/L (HR: 1.452; 95% CI: 1.014–2.079), 4.80–5.49 mmol/L (HR: 2.151; 95% CI: 1.427–3.241), and ≥5.50 mmol/L (HR: 2.341; 95% CI: 1.514–3.620) had an increased risk of all-cause mortality. ConclusionIncreased serum K+ levels, including levels of 4.10–5.49 mmol/L and ≥5.50 mmol/L, were associated with a significantly increased short- and long-term risk of death. Serum K+ has the potential to be a marker of disease severity among very elderly patients with AKI.

Potassium Effects on NCC Are Attenuated during Inhibition of Cullin E3-Ubiquitin Ligases.

The thiazide-sensitive sodium chloride cotransporter (NCC) plays a vital role in maintaining sodium (Na+) and potassium (K+) homeostasis. NCC activity is modulated by with-no-lysine kinases 1 and 4 (WNK1 and WNK4), the abundance of which is controlled by the RING-type E3 ligase Cullin 3 (Cul3) and its substrate adapter Kelch-like protein 3. Dietary K+ intake has an inverse correlation with NCC activity, but the mechanism underlying this phenomenon remains to be fully elucidated. Here, we investigated the involvement of other members of the cullin family in mediating K+ effects on NCC phosphorylation (active form) and abundance. In kidneys from mice fed diets varying in K+ content, there were negative correlations between NCC (phosphorylated and total) and active (neddylated) forms of cullins (Cul1, 3, 4, and 5). High dietary K+ effects on phosphorylated NCC were attenuated in Cul3 mutant mice (CUL3-Het/Δ9). Short-term (30 min) and long-term (24 h) alterations in the extracellular K+ concentration did not affect cullin neddylation levels in ex vivo renal tubules. In the short term, the ability of high extracellular K+ to decrease NCC phosphorylation was preserved in the presence of MLN4924 (pan-cullin inhibitor), but the response to low extracellular K+ was absent. In the long term, MLN4924 attenuated the effects of high extracellular K+ on NCC phosphorylation, and responses to low extracellular K+ were absent. Our data suggest that in addition to Cul3, other cullins are involved in mediating the effects of K+ on NCC phosphorylation and abundance.

Alterations of Ion Homeostasis in Cancer Metastasis: Implications for Treatment.

We have previously reported that metastases from all malignancies are characterized by a core program of gene expression that suppresses extracellular matrix interactions, induces vascularization/tissue remodeling, activates the oxidative metabolism, and alters ion homeostasis. Among these features, the least elucidated component is ion homeostasis. Here we review the literature with the goal to infer a better mechanistic understanding of the progression-associated ionic alterations and identify the most promising drugs for treatment. Cancer metastasis is accompanied by skewing in calcium, zinc, copper, potassium, sodium and chloride homeostasis. Membrane potential changes and water uptake through Aquaporins may also play roles. Drug candidates to reverse these alterations are at various stages of testing, with some having entered clinical trials. Challenges to their utilization comprise differences among tumor types and the involvement of multiple ions in each case. Further, adverse effects may become a concern, as channel blockers, chelators, or supplemented ions will affect healthy and transformed cells alike.

Phospholipase Dα1 Acts as a Negative Regulator of High Mg2+-Induced Leaf Senescence in Arabidopsis.

Magnesium (Mg2+) is a macronutrient involved in essential cellular processes. Its deficiency or excess is a stress factor for plants, seriously affecting their growth and development and therefore, its accurate regulation is essential. Recently, we discovered that phospholipase Dα1 (PLDα1) activity is vital in the stress response to high-magnesium conditions in Arabidopsis roots. This study shows that PLDα1 acts as a negative regulator of high-Mg2+-induced leaf senescence in Arabidopsis. The level of phosphatidic acid produced by PLDα1 and the amount of PLDα1 in the leaves increase in plants treated with high Mg2+. A knockout mutant of PLDα1 (pldα1-1), exhibits premature leaf senescence under high-Mg2+ conditions. In pldα1-1 plants, higher accumulation of abscisic and jasmonic acid (JA) and impaired magnesium, potassium and phosphate homeostasis were observed under high-Mg2+ conditions. High Mg2+ also led to an increase of starch and proline content in Arabidopsis plants. While the starch content was higher in pldα1-1 plants, proline content was significantly lower in pldα1-1 compared with wild type plants. Our results show that PLDα1 is essential for Arabidopsis plants to cope with the pleiotropic effects of high-Mg2+ stress and delay the leaf senescence.

The small GTPase RABA2a recruits SNARE proteins to regulate the secretory pathway in parallel with the exocyst complex in Arabidopsis

Delivery of proteins to the plasma membrane occurs via secretion, which requires tethering, docking, priming, and fusion of vesicles. In yeast and mammalian cells, an evolutionarily conserved RAB GTPase activation cascade functions together with the exocyst and SNARE proteins to coordinate vesicle transport with fusion at the plasma membrane. However, it is unclear whether this is the case in plants. In this study, we show that the small GTPase RABA2a recruits and interacts with the VAMP721/722-SYP121-SNAP33 SNARE ternary complex for membrane fusion. Through immunoprecipitation coupled with mass spectrometry analysis followed by the validatation with a series of biochemical assays, we identified the SNARE proteins VAMP721 and SYP121 as the interactors and downstream effectors of RABA2a. Further expreiments showed that RABA2a interacts with all members of the SNARE complex in its GTP-bound form and modulates the assembly of the VAMP721/722-SYP121-SNAP33 SNARE ternary complex. Intriguingly, we did not observe the interaction of the exocyst subunits with either RABA2a or theSNARE proteins in several different experiments. Neither RABA2a inactivation affects the subcellular localization or assembly of the exocystnor the exocyst subunit mutant exo84b shows the disrupted RABA2a-SNARE association or SNARE assembly, suggesting that the RABA2a-SNARE- and exocyst-mediated secretory pathways are largely independent. Consistently, our live imaging experiments reveal that the two sets of proteins follow non-overlapping trafficking routes, and genetic and cell biologyanalyses indicate that the two pathways select different cargos. Finally, we demonstrate that the plant-specific RABA2a-SNARE pathway is essential for the maintenance of potassium homeostasis in Arabisopsis seedlings. Collectively, our findings imply that higher plants might have generated different endomembrane sorting pathways during evolution and may enable the highly conserved endomembrane proteins to participate in plant-specific trafficking mechanisms for adaptation to the changing environment.

Aldosterone and dexamethasone activate African lungfish mineralocorticoid receptor: Increased activation after removal of the amino-terminal domain

Aldosterone, the main physiological mineralocorticoid in humans and other terrestrial vertebrates, first appears in lungfish, which are lobe-finned fish that are forerunners of terrestrial vertebrates. Aldosterone activation of the MR regulates internal homeostasis of water, sodium and potassium, which was critical in the conquest of land by vertebrates. We studied transcriptional activation of the slender African lungfish MR by aldosterone, other corticosteroids and progesterone and find that aldosterone, 11-deoxycorticosterone, 11-deoxycortisol and progesterone have half-maximal responses (EC50 s) below 1 nM and are potential physiological mineralocorticoids. In contrast, EC50 s for corticosterone and cortisol were 23 nM and 66 nM, respectively. Unexpectedly, truncated lungfish MR, consisting of the DNA-binding, hinge and steroid-binding domains, had a stronger response to corticosteroids and progesterone than full-length lungfish MR, indicating that the N-terminal domain represses steroid activation of lungfish MR, unlike human MR in which the N-terminal domain contains an activation function. BLAST searches of GenBank did not retrieve a GR ortholog, leading us to test dexamethasone and triamcinolone for activation of lungfish MR. At 10 nM, both synthetic glucocorticoids are about 4-fold stronger than 10 nM aldosterone in activating full-length lungfish MR, leading us to propose that lungfish MR also functions as a GR.

Evolution of inwardly rectifying potassium channels and their gene expression in zebrafish embryos.

Inwardly rectifying potassium channels are essential for normal potassium homeostasis, maintaining the cellular resting membrane potential, and regulating electrolyte transportation. Mutations in Kir channels have been known to cause debilitating diseases ranging from neurological abnormalities to renal and cardiac failures. Many efforts have been made to understand their protein structures, physiological functions, and pharmacological modifiers. However, their expression and functions during embryonic development remain largely unknown. Using zebrafish as a model, we identified and renamed 31 kir genes. We also analyzed Kir gene evolution by phylogenetic and syntenic analyses. Our data indicated that the four subtypes of the Kir genes might have already evolved out in chordates. These vertebrate Kir genes most likely resulted from both whole-genome duplications and tandem duplications. In addition, we examined zebrafish kir gene expression during early embryogenesis. Each subgroup's genes showed similar but distinct gene expression domains. The gene expression of ohnologous genes from teleost-specific whole-genome duplication indicated subfunctionalization. Varied temporal gene expression domains suggest that Kir channels may be needed for embryonic patterning or regulation. Our phylogenetic and developmental analyses of Kir channels shed light on their evolutionary history and potential functions during embryogenesis related to congenital diseases and human channelopathies.

Role of collecting duct principal cell NOS1β in sodium and potassium homeostasis.

The nitric oxide (NO)‐generating enzyme, NO synthase‐1β (NOS1β), is essential for sodium (Na+) homeostasis and blood pressure control. We previously showed that collecting duct principal cell NOS1β is critical for inhibition of the epithelial sodium channel (ENaC) during high Na+ intake. Previous studies on freshly isolated cortical collecting ducts (CCD) demonstrated that exogenous NO promotes basolateral potassium (K+) conductance through basolateral channels, presumably Kir4.1 (Kcnj10) and Kir5.1 (Kcnj16). We, therefore, investigated the effects of NOS1β knockout on Kir4.1/Kir5.1 channel activity. Indeed, in CHO cells overexpressing NOS1β and Kir4.1/Kir5.1, the inhibition of NO signaling decreased channel activity. Male littermate control and principal cell NOS1β knockout mice (CDNOS1KO) on a 7‐day, 4% NaCl diet (HSD) were used to detect changes in basolateral K+ conductance. We previously demonstrated that CDNOS1KO mice have high circulating aldosterone despite a high‐salt diet and appropriately suppressed renin. We observed greater Kir4.1 cortical abundance and significantly greater Kir4.1/Kir5.1 single‐channel activity in the principal cells from CDNOS1KO mice. Moreover, blocking aldosterone action with in vivo spironolactone treatment resulted in lower Kir4.1 abundance and greater plasma K+ in the CDNOS1KO mice compared to controls. Lowering K+ content in the HSD prevented the high aldosterone and greater plasma Na+ of CDNOS1KO mice and normalized Kir4.1 abundance. We conclude that during chronic HSD, lack of NOS1β leads to increased plasma K+, enhanced circulating aldosterone, and activation of ENaC and Kir4.1/Kir5.1 channels. Thus, principal cell NOS1β is required for the regulation of both Na+ and K+ by the kidney.

Hyperkalemia management in the emergency department: An expert panel consensus.

Hyperkalemia is a common electrolyte abnormality identified in the emergency department (ED) and potentially fatal. However, there is no consensus over the potassium threshold that warrants intervention or its treatment algorithm. Commonly used medications are at best temporizing measures, and the roles of binders are unclear in the emergent setting. As the prevalence of comorbid conditions altering potassium homeostasis rises, hyperkalemia becomes more common, and hence there is a need to standardize management. A panel was assembled to synthesize the available evidence and identify gaps in knowledge in hyperkalemia treatment in the ED. The panel was composed of 7 medical practitioners, including 5 physicians, a nurse, and a clinical pharmacist with collective expertise in the areas of emergency medicine, nephrology, and hospital medicine. This panel was sponsored by the American College of Emergency Physicians with a goal to create a consensus document for managing acute hyperkalemia. The panel evaluated the evidence on calcium for myocyte stabilization and potassium shifting and excretion. This article summarizes information on available therapies for hyperkalemia and proposes a hyperkalemia treatment algorithm for the ED practitioner based on the currently available literature and highlights diagnostic pitfalls and evidence gaps.

Effectiveness of Sodium Zirconium Cyclosilicate in Hemodialysis Patients With Severe Hyperkalemia

Effectiveness of Sodium Zirconium Cyclosilicate in Hemodialysis Patients With Severe Hyperkalemia

Proanthocyanidins Maintain Cardiac Ionic Homeostasis in Aldosterone-Induced Hypertension and Heart Failure.

Excess aldosterone promotes pathological remodeling of the heart and imbalance in cardiac ion homeostasis of sodium, potassium and calcium. Novel treatment with proanthocyanidins in aldosterone-treated rats has resulted in downregulation of cardiac SGK1, the main genomic aldosterone-induced intracellular mediator of ion handling. It therefore follows that proanthocyanidins could be modulating cardiac ion homeostasis in aldosterone-treated rats. Male Wistar rats received aldosterone (1 mg kg−1 day−1) +1% NaCl for three weeks. Half of the animals in each group were simultaneously treated with the proanthocyanidins-rich extract (80% w/w) (PRO80, 5 mg kg−1 day−1). PRO80 prevented cardiac hypertrophy and decreased calcium content. Expression of ion channels (ROMK, NHE1, NKA and NCX1) and calcium transient mediators (CAV1.2, pCaMKII and oxCaMKII) were reduced by PRO80 treatment in aldosterone-treated rats. To conclude, our data indicate that PRO80 may offer an alternative treatment to conventional MR-blockade in the prevention of aldosterone-induced cardiac pathology.

BusR senses bipartite DNA binding motifs by a unique molecular ruler architecture.

The cyclic dinucleotide second messenger c-di-AMP is a major player in regulation of potassium homeostasis and osmolyte transport in a variety of bacteria. Along with various direct interactions with proteins such as potassium channels, the second messenger also specifically binds to transcription factors, thereby altering the processes in the cell on the transcriptional level. We here describe the structural and biochemical characterization of BusR from the human pathogen Streptococcus agalactiae. BusR is a member of a yet structurally uncharacterized subfamily of the GntR family of transcription factors that downregulates transcription of the genes for the BusA (OpuA) glycine-betaine transporter upon c-di-AMP binding. We report crystal structures of full-length BusR, its apo and c-di-AMP bound effector domain, as well as cryo-EM structures of BusR bound to its operator DNA. Our structural data, supported by biochemical and biophysical data, reveal that BusR utilizes a unique domain assembly with a tetrameric coiled-coil in between the binding platforms, serving as a molecular ruler to specifically recognize a 22 bp separated bipartite binding motif. Binding of c-di-AMP to BusR induces a shift in equilibrium from an inactivated towards an activated state that allows BusR to bind the target DNA, leading to transcriptional repression.

Contribution of Neuronal and Glial Two-Pore-Domain Potassium Channels in Health and Neurological Disorders.

Two-pore-domain potassium (K2P) channels are widespread in the nervous system and play a critical role in maintaining membrane potential in neurons and glia. They have been implicated in many stress-relevant neurological disorders, including pain, sleep disorder, epilepsy, ischemia, and depression. K2P channels give rise to leaky K+ currents, which stabilize cellular membrane potential and regulate cellular excitability. A range of natural and chemical effectors, including temperature, pressure, pH, phospholipids, and intracellular signaling molecules, substantially modulate the activity of K2P channels. In this review, we summarize the contribution of K2P channels to neuronal excitability and to potassium homeostasis in glia. We describe recently discovered functions of K2P channels in glia, such as astrocytic passive conductance and glutamate release, microglial surveillance, and myelin generation by oligodendrocytes. We also discuss the potential role of glial K2P channels in neurological disorders. In the end, we discuss current limitations in K2P channel researches and suggest directions for future studies.

Supplementation of taurine improves ionic homeostasis and mitochondrial function in the rats exhibiting post-traumatic stress disorder-like symptoms

RationaleCurrent pharmacotherapy for post-traumatic stress disorder (PTSD) is limited to few antidepressants. Mitochondrial dysfunction is observed in PTSD, along with altered potassium homeostasis. Nutritional supplementation of taurine can improve ionic homeostasis and thereby treat PTSD-like symptoms in rats. AimThe purpose is to study the pharmacological effect of taurine in stress re-stress-induced PTSD in rats. MethodsAs per protocol, animals were restrained for 2 h then exposed to footshock (FS) (2 mA/10 s) followed by halothane-induced anesthesia. Behavioral assessments such as elevated plus maze (EPM) and Y-maze tests were performed on days 2, 8, and 32 of experimental protocol after re-stress. In addition, daily oral administration of taurine (100, 200, and 300 mg/kg) and paroxetine (PAX) (10 mg/kg) was done from D-8 to D-32 followed by re-stress. The plasma concentration of taurine, corticosterone, and potassium was measured on Day-32 along with mitochondrial function in discrete brain regions. ResultsSub-chronic administration of taurine in high and medium doses significantly ameliorated PTSD-like symptoms such as hyperarousal, anxiety, and improved spatial recognition memory. Taurine in all doses restored the plasma concentration of corticosterone and potassium. SRS-induced alterations in mitochondrial bioenergetics, complex enzyme activities, and reduced mitochondrial membrane potential in different brain regions were ameliorated by taurine. ConclusionNutritional supplementation of taurine improves potassium ionic homeostasis, mitochondrial function, and attenuated PTSD-like symptoms in SRS subjected rats.