Na^(+)/K^(+)-ATPase:ion pump,signal transducer,or cytoprotective protein,and novel biological functions

Na^(+)/K^(+)-ATPase is a transmembrane protein that has important roles in the maintenance of electrochemical gradients across cell membranes by transporting three Na^(+)out of and two K^(+)into cells.Additionally,Na^(+)/K^(+)-ATPase participates in Ca^(2+)-signaling transduction and neurotransmitter release by coordinating the ion concentration gradient across the cell membrane.Na^(+)/K^(+)-ATPase works synergistically with multiple ion channels in the cell membrane to form a dynamic network of ion homeostatic regulation and affects cellular communication by regulating chemical signals and the ion balance among different types of cells.Therefo re,it is not surprising that Na^(+)/K^(+)-ATPase dysfunction has emerged as a risk factor for a variety of neurological diseases.However,published studies have so far only elucidated the important roles of Na^(+)/K^(+)-ATPase dysfunction in disease development,and we are lacking detailed mechanisms to clarify how Na^(+)/K^(+)-ATPase affects cell function.Our recent studies revealed that membrane loss of Na^(+)/K^(+)-ATPase is a key mechanism in many neurological disorders,particularly stroke and Parkinson's disease.Stabilization of plasma membrane Na^(+)/K^(+)-ATPase with an antibody is a novel strategy to treat these diseases.For this reason,Na^(+)/K^(+)-ATPase acts not only as a simple ion pump but also as a sensor/regulator or cytoprotective protein,participating in signal transduction such as neuronal autophagy and apoptosis,and glial cell migration.Thus,the present review attempts to summarize the novel biological functions of Na^(+)/K^(+)-ATPase and Na^(+)/K^(+)-ATPase-related pathogenesis.The potential for novel strategies to treat Na^(+)/K^(+)-ATPase-related brain diseases will also be discussed.

Plant salt tolerance and Na^+ sensing and transport

Salinity is a global challenge to agricultural production. Understanding Na^+ sensing and transport in plants under salt stress will be of benefit for breeding robustly salt-tolerant crop species. In this review, first, possible salt stress sensor candidates and the root meristem zone as a tissue harboring salt stress-sensing components are proposed. Then,the importance of Na^+ exclusion and vacuolar Na^+ sequestration in plant overall salt tolerance is highlighted. Other Na^+ regulation processes, including xylem Na^+ loading and unloading, phloem Na^+ recirculation, and Na^+ secretion, are discussed and summarized.Along with a summary of Na^+ transporters and channels, the molecular regulation of Na^+ transporters and channels in response to salt stress is discussed. Finally, some largely neglected issues in plant salt stress tolerance, including Na^+ concentration in cytosol and the role of Na^+ as a nutrient, are reviewed and discussed.

Roles of Na^+/Ca^(2+) exchanger 1 in digestive system physiology and pathophysiology

The Na^+/Ca^(2+) exchanger(NCX) protein family is a part of the cation/Ca^(2+) exchanger superfamily and participates in the regulation of cellular Ca^(2+) homeostasis. NCX1, the most important subtype in the NCX family, is expressed widely in various organs and tissues in mammals and plays an especially important role in the physiological and pathological processes of nerves and the cardiovascular system. In the past few years, the function of NCX1 in the digestive system has received increasing attention; NCX1 not only participates in the healing process of gastric ulcer and gastric mucosal injury but also mediates the development of digestive cancer, acute pancreatitis, and intestinal absorption.This review aims to explore the roles of NCX1 in digestive system physiology and pathophysiology in order to guide clinical treatments.

Arsenic exposure decreases rhythmic contractions of vascular tone through sodium transporters and K^+ channels

Arsenic-contaminated drinking water is a public health problem in countries such as Taiwan, Bangladesh, United States, Mexico, Argentina, and Chile. The chronic ingestion of arsenic-contaminated drinking water increases the risk for ischemic heart disease, cerebrovascular disease, and prevalence of hypertension. Although toxic arsenic effects are controversial, there is evidence that a high concentration of arsenic may induce hypertension through increase in vascular tone and resistance. Vascular tone is regulated by the rhythmic contractions of the blood vessels, generated by calcium oscillations in the cytosol of vascular smooth muscle cells. To regulate the cytosolic calcium oscillations, the membrane oscillator model involves the participation of Ca2+ channels, calcium-activated K+ channels, Na+/Ca2+exchange, plasma membrane Ca2+-ATPase, and the Na+/K+-ATPase. However, little is known about the role of K+ uptake by sodium transporters [Na+/K+-ATPase or Na+-K+-2Cl-(NKCC1)] on the rhythmic contractions.Vascular rhythmic contractions, or vasomotion are a local mechanism to regulate vascular resistance andblood flow. Since vascular rhythmic contractions of blood vessels are involved in modulating the vascular resistance, the blood flow, and the systemic pressure,we suggest a model explaining the participation of the sodium pump and NKCC1 co-transporter in low dose arsenic exposure effects on vasomotion and vascular dysfunction.

Blockade of Na^+/H^+ exchanger type 3 causes intracellular acidification and hyperexcitability via inhibition of pH-sensitive K^+ channels in chemosensitive respiratory neurons of the dorsal vagal nucleus in rats

Extracellular pH （pHe） and intracellular pH （pHi） are important factors for the excitability of chemosensitive central respiratory neurons that play an important role in respiration and obstructive sleep apnea. It has been proposed that inhibition of central Na^＋/ H^＋ exchanger 3 （NHE-3）, a key pHi regulator in the brainstem, decreases the pH, leading to membrane depolarization for the maintenance of respiration. However, how intracellular pH affects the neuronal excitability of respiratory neurons remains largely unknown. In this study, we showed that NHE-3 mRNA is widely distributed in respiration-related neurons of the rat brainstem, including the dorsal vagal nucleus （DVN）. Whole-cell patch clamp recordings from DVN neurons in brain slices revealed that the standing outward current （Iso） through pH-sensitive K^＋ channels was inhibited in the presence of the specific NHE-3 inhibitor AVE0657 that decreased the pHi. Exposure of DVN neurons to an acidified PIle and AVE0657 （5 μmol/L） resulted in a stronger effect on firing rate and Iso than acidified pHe alone. Taken together, our results showed that intracellular acidification by blocking NHE-3 results in inhibition of a pH- sensitive K^＋ current, leading to synergistic excitation of chemosensitive DVN neurons for the regulation of respiration.

Rationally designed graphene channels for real-time sodium ion detection for electronic tongue

Monitoring taste-inducing ions and molecules continuously in liquids or solutions is of great considerable matter for the realization of the electronic tongue(E-tongue).Particularly from the five major tastes,the highly selective,sensitive detection of Na^(+)in real-time is prioritized.Prioritization is due to the saltiness of food is the key ingredient in most meals.Nevertheless,existing Na^(+)detecting devices have relatively low performances of selectivity,sensitivity,and lack of on–off functions.Additionally,conventional devices significantly deteriorate in capac-ity due to repetitive usage or lifetime shortage by degradation of the sensing mate-rial.Herein,a graphene-based channel was rationally designed by the facile decoration of Calix[4]arene and Nafion to address this issue.They act as a receptor and a molecular sieve,respectively,to enhance selectivity and sensitivity and elon-gate the life expectancy of the device.This device was merged with a microfluidic channel to control the injection and withdrawal of solutions to fulfill dynamic on–off functions.The fabricated device has highly selective,sensitive Na^(+)detection properties compared to other 10 molecule/ionic species.Dynamic on–off functions of the device were available,also possesses a long lifespan of at least 220 days.Additionally,it can precisely discriminate real beverages containing Na^(+),which can be observed by principal component analysis plot.These features offer the possibility of ascending to a platform for E-tongues in near future.

Tityus serrulatus venom and its toxins Ts1 and Ts5 increase cytosolic Ca^(2+)concentration in isolated vascular smooth muscle cells

Voltage-gated Na+ channel (Nav channel) scorpion toxins are classified as α- and β-neurotoxins. Ts5 (α-neurotoxin) and Ts1 (β-neurotoxin) from Tityus serrulatus venom (TsV) interact with Nav channels, increasing Na+ influx and activating voltage-dependent Ca2+ channels. This study aimed to investigate the effect of TsV, Ts1 and Ts5 on the cytosolic Ca2+ concentration ([Ca2+]C) in rat aortic smooth muscle cells. Toxins were isolated by ion exchange chromatography (Ts1) followed by RP-HPLC (Ts5). The rat aortic smooth muscle cells were isolated in Hanks buffer pH 7.4 and loaded with 5 μmol/L of Fura-2AM (45 minutes at 37℃), in order to measure [Ca2+]C by fluorescence of Fura-2/AM (ratio 340/380 nm). The fluorescence was measured in one single cell (excitation: 340 and 380 nm;emission: 510 nm). TsV (100 and 500 mg/mL) and its toxins Ts1 and Ts5 (50 and 100 mg/mL each) led to a concentration-dependent increase in [Ca2+]C. Tetrodotoxin (1 mmol/L), a Nav channel blocker, and verapamil (1 mmol/L), a voltage-operated Ca2+ channel blocker, inhibited the increase in [Ca2+]C induced by TsV (500 mg/mL). In conclusion, TsV and its toxins induce a concentration-dependent increase in [Ca2+]C that probably occurs through interaction with Nav channels, thus inducing depolarization and consequent Ca2+ influx. This assumption is based on the fact that this effect is inhibited by tetrodotoxin and verapamil, showing a direct action of TsV toxins on aorta smooth muscle cells.

δ-opioid Receptor Induced Inhibition of Sodium Channel Function

Objective： To study the precise role of DOR in the regulation of sodium channels at present. Methods： With Xenopus oocytes co-expressing sodium channel subtype 2 （Nav1.2） and DOR. Results： 1） Nav1.2 expression induced tetrodotoxin-sensitive inward currents; 2） DOR expression reduced the inward currents; 3） activation of DOR reduced the amplitude of the current and rightly shifted the activation curve of the current in the oocytes with both Nav1.2 and DOR, but not in ones with Nav1.2 alone; 4） the DOR agonist-induced inhibition of Nay 1.2 currents was in a dose-dependent manner and saturable; 5） the DOR agonist had no effect on naive oocytes. Conclusion： These data represent the first demonstration that activation of DOR inhibits Na^＋ channel function by decreasing the amplitude of sodium currents and increasing its threshold of activation. This novel finding has far-reaching impacts on novel solutions of certain neurological disorders such as hypoxic/ischemic injury, epilepsy and pain. Also, our data may improve the understanding of the mechanisms underlying acupuncture since acupuncture is known to activate the brain opioid system.

A binding-block ion selective mechanism revealed by a Na/K selective channel

Mechanosensitive （MS） channels are extensively stud- ied membrane protein for maintaining intracellular homeostasis through translocating solutes and ions across the membrane, but its mechanisms of channel gating and ion selectivity are largely unknown. Here, we identified the Ynal channel as the Na^＋/K^＋ cation-selec- tive MS channel and solved its structure at 3.8 A by cryo- EM single-particle method. Ynal exhibits low conduc- tance among the family of MS channels in E. coil, and shares a similar overall heptamer structure fold with previously studied MscS channels. By combining structural based mutagenesis, quantum mechanical and electrophysiological characterizations, we revealed that ion selective filter formed by seven hydrophobic methionine （Ynal^Met158） in the transmembrane pore determined ion selectivity, and both ion selectivity and gating of Ynal channel were affected by accompanying anions in solution. Further quantum simulation and functional validation support that the distinct binding energies with various anions to Ynal^Met158 facilitate Na^＋/K^＋ pass through, which was defined as binding-block mechanism. Our structural and functional studies provided a new perspective for understanding the mechanism of how MS channels select ions driven by mechanical force.