The sodium/calcium exchanger family-SLC8

The Na(+)/Ca(2+) exchanger gene family encompasses three distinct proteins, NCX1, NCX2, and NCX3, which mediate cellular Ca(2+) efflux and thus contribute to intracellular Ca(2+) homeostasis. NCX1 is expressed ubiquitously while NCX2 and NCX3 are limited to brain and skeletal muscle. NCX1 exchanges 3 extracellular Na(+) for 1 intracellular Ca(2+). In addition to transporting Na(+) and Ca(2+), NCX1 activity is also regulated by these cations. NCX1 is especially important in regulating cardiac contractility.     

Sodium/calcium exchange: its physiological implications.

The Na+/Ca2+ exchanger, an ion transport protein, is expressed in the plasma membrane (PM) of virtually all animal cells. It extrudes Ca2+ in parallel with the PM ATP-driven Ca2+ pump. As a reversible transporter, it also mediates Ca2+ entry in parallel with various ion channels. The energy for net Ca2+ transport by the Na+/Ca2+ exchanger and its direction depend on the Na+, Ca2+, and K+ gradients across the PM, the membrane potential, and the transport stoichiometry. In most cells, three Na+ are exchanged for one Ca2+. In vertebrate photoreceptors, some neurons, and certain other cells, K+ is transported in the same direction as Ca2+, with a coupling ratio of four Na+ to one Ca2+ plus one K+. The exchanger kinetics are affected by nontransported Ca2+, Na+, protons, ATP, and diverse other modulators. Five genes that code for the exchangers have been identified in mammals: three in the Na+/Ca2+ exchanger family (NCX1, NCX2, and NCX3) and two in the Na+/Ca2+ plus K+ family (NCKX1 and NCKX2). Genes homologous to NCX1 have been identified in frog, squid, lobster, and Drosophila. In mammals, alternatively spliced variants of NCX1 have been identified; dominant expression of these variants is cell type specific, which suggests that the variations are involved in targeting and/or functional differences. In cardiac myocytes, and probably other cell types, the exchanger serves a housekeeping role by maintaining a low intracellular Ca2+ concentration; its possible role in cardiac excitation-contraction coupling is controversial. Cellular increases in Na+ concentration lead to increases in Ca2+ concentration mediated by the Na+/Ca2+ exchanger; this is important in the therapeutic action of cardiotonic steroids like digitalis. Similarly, alterations of Na+ and Ca2+ apparently modulate basolateral K+ conductance in some epithelia, signaling in some special sense organs (e.g., photoreceptors and olfactory receptors) and Ca2+-dependent secretion in neurons and in many secretory cells. The juxtaposition of PM and sarco(endo)plasmic reticulum membranes may permit the PM Na+/Ca2+ exchanger to regulate sarco(endo)plasmic reticulum Ca2+ stores and influence cellular Ca2+ signaling.     

Sodium/calcium exchange regulates cytoplasmic calcium in smooth muscle

The sodium/calcium (Na⁺/Ca²⁺) exchanger is often considered to be a key regulator of the cytoplasmic calcium concentration ([Ca²⁺]) in smooth muscle but neither its precise role in Ca²⁺ homeostasis nor even its existence in smooth muscle are generally agreed upon. Here we directly assessed the role Na⁺/Ca²⁺ exchange plays in regulating [Ca²⁺] in single voltage-clamped smooth muscle cells. Following an elevation of [Ca²⁺], its decline was found to have both voltage-dependent and voltage-independent components. The voltage-dependent component was abolished when Na⁺ was removed from the external bathing solution. During the fall of [Ca²⁺] a small and declining Na⁺-dependent inward current was observed of a magnitude predicted by 31 Na⁺/Ca²⁺ exchange stoichiometry. At [Ca²⁺] above 400 nM the principal efflux of Ca²⁺ above rest was attributed to this Na⁺-dependent removal mechanism. These results establish that a Na⁺/Ca²⁺ exchanger exists in smooth muscle and argue that it can regulate [Ca²⁺] at physiological Ca²⁺ concentrations.     

心肌肽素抗心律失常作用及对钙和钾离子通道的影响

目的：观察心肌肽素对室速、室颤发生率及心室肌细胞钙、钾电流的影响。方法：建立整体动物心肌缺血－再灌流损伤模型。以膜片钳技术记录单个心室肌细胞内向钙电流及电流－电压曲线、内向整流钾电流及延迟整流钾电流。结果：心肌肽素可降低低室速、室颤发生率,在一定浓度下对心肌细胞内向钙向电流有明显的抑制作用,且该作用具有一定的电压依赖性,而对内向整流钾电流及延迟整流钾电流均无作用。结论：心肌肽素能降低缺血－再灌流损     

生长抑素对人脐静脉内皮细胞Ca2+及其膜通道的调控研究

目的观察生长抑素(SOM)对人脐静脉内皮细胞(HUVEC)膜上Ca2+通道及胞浆内游离Ca2+浓度([Ca2+]i)的调控作用.方法应用共聚焦激光扫描显微术(CLSM)和膜片钳单通道记录技术对体培养HUVEC胞浆内[Ca2+]i、膜上Ca2+通道开放情况进行观察.结果SOM促使HUVEC胞浆内[Ca2+]i明显升高.胞膜上Ca2+通道的开放出现1～2 min的潜伏期后也开放但其开放概率明显降低.结论SOM对HUVEC胞浆内[Ca2+]i的调节可能首先通过细胞内储存的Ca2+释放及稍后的细胞膜上Ca2+通道开放,从而达到其调节效应.     

生长抑素对人脐静脉内皮细胞Ca2+及其膜通道的调控研究

目的：观察生长抑素(SOM)对人脐静脉内皮细胞(HUVEC)膜上Ca2 通道及脑浆内游离Ca2 浓度([Ca2 ]i)的调控作用。方法：应用共聚焦激光扫描显微术(CLSM)和膜片钳单通道记录技术对体培养HUVEC脑浆内[Ca2 ]i、膜上Ca2 通道开放情况进行观察。结果：SOM促使HUVEC脑浆内[Ca2 ]i明显升高。胞膜上Ca2 通道的开放出现l-2min的潜伏期后也开放但其开放概率明显降低。结论：SOM对HUVEC脑浆内[Ca2 ]i的调节可能首先通过细胞内储存的Ca2 释放及稍后的细胞膜上Ca2 通道开放，从而达到其调节效应。     

Comparative transcriptome analysis of the calcium signaling and expression analysis of sodium/calcium exchanger in Aspergillus cristatus

Aspergillus cristatus develops into various stages under different Na concentrations: the sexual stage in 0.5 M NaCl and asexual development stage in 3 M NaCl. In order to explore whether the Ca²⁺ signaling pathway in A. cristatus responded to the changes in the salt stress, we analyzed the gene expression levels in A. cristatus respectively cultured in 0.5 M NaCl and 3 M NaCl. According to the BLAST analysis results, we identified 25 Ca²⁺‐signaling proteins in A. cristatus. The expression levels of most genes involved in the Ca²⁺‐signaling pathway in A. cristatus cultured in different salt concentrations showed significant differences, indicating that the Ca²⁺ signaling pathway was involved in the response to the changes in the salt stress. In yeasts, only calcium ion influx proteins were reported to be involved in the response to the changes in the salt stress. So far, the protein for the exchanger of calcium/sodium ions has not been reported. Therefore, we obtained the sodium/calcium exchanger (termed NCX) proteins from the KEGG Database. The ncx gene of A. cristatus was cloned and characterized. The full length of ncx gene is 3055 bp, including a 2994‐bp open reading frame encoding 994 amino acids. The expression levels of ncx in the sexual development stage and asexual development stage were respectively ～8.94 times and ～2.57 times of that in the hyphal formation stage. Therefore, we suggested that ncx gene was up‐regulated to resist the sodium stress. The study results provide the basis for further exploring the Ca²⁺‐signaling mechanism and ion exchanger mechanism.     

Sodium-calcium exchanger (NCX-1) and calcium modulation: NCX protein expression patterns and regulation of early heart development.

Ouabain-induced inhibition of early heart development indicated that Na/K-ATPase plays an important role in maintaining normal ionic balances during differentiation of cardiomyocytes (Linask and Gui [1995] Dev Dyn 203:93-105). Inhibition of the sodium pump is generally accepted to affect the activity of the Na(+)-Ca(++) exchanger (NCX) to increase intracellular [Ca(++)]. These previous findings suggested that Ca(++) signaling may be an important modulator during differentiation of cardiomyocytes. In order to identify a connection between heart development and NCX-mediated Ca(++) regulation, we determined the embryonic spatiotemporal protein expression pattern of NCX-1 during early developmental stages. In both chick and mouse embryos, NCX-1 (the cardiac NCX isoform) is asymmetrically expressed during gastrulation; in the right side of the Hensen's node in the chick, in the right lateral mesoderm in the mouse. At slightly later stages, NCX-1 is expressed in the heart fields at comparable stages of heart development, in the chick at stage 7 and in the mouse at embryonic day (ED) 7.5. By ED 8 in the mouse, the exchanger protein displays a rostrocaudal difference in cardiac expression and an outer curvature-inner curvature ventricular difference. By ED 9.5, cardiac expression has increased from that seen at ED8 and NCX-1 is distributed throughout the myocardium consistent with the possibility that it is important in regulating initial cardiac contractile function. Only a low level of expression is detected in inflow and outflow regions. To substantiate a role for the involvement of calcium-mediated signaling, using pharmacologic approaches, ionomycin (a Ca(++) ionophore) was shown to perturb cardiac cell differentiation in a manner similar to ouabain as assayed by cNkx2.5 and sarcomeric myosin heavy chain expression. In addition, we show that an inhibitor of NCX, KB-R7943, can similarly and adversely affect early cardiac development at stage 4/5 and arrests cardiac cell contractility in 12-somite embryos. Thus, based upon NCX-1 protein expression patterns in the embryo, experimental Ca(++) modulation, and inhibition of NCX activity by KB-R7943, these results suggest an early and central role for calcium-mediated signaling in cardiac cell differentiation and NCX's regulation of the initial heartbeats in the embryo.     

Biphasic calcium phosphates: influence of three synthesis parameters on the HA/beta-TCP ratio

Hydroxyapatite (HA) contents measurements were conducted on eight biphasic calcium phosphate (BCP) samples obtained by sintering calcium-deficient apatite formed previously by hydrolyzing a dicalcium phosphate dihydrate (DCPD) powder. We evaluated the influences and interactions of three synthesis factors: alkalinity, process duration, and concentration of the water suspension in DCPD. Those parameters were varied simultaneously between two limit levels. Experiments used a factorial design method (FDM) allowing optimization of the number of samples as well as statistical analysis of results. FDM showed that HA content, in a defined experimental area, can be described by a first-order polynomial equation in which the initial alcalinity and the DCPD/water ratio are the major influences. Experiment prove that pH measured at the end of the hydrolysis was predictive of the HA content in the final BCP. This study leads up to an isoresponse line diagram which will allow the synthesis of some BCP with fitted HA/beta-tricalcium phosphate ratios.     

Sodium ions, calcium ions, blood pressure regulation, and hypertension: a reassessment and a hypothesis.

An attempt is made to elucidate the cellular mechanisms which may account for the well-documented correlation between sodium metabolism and peripheral vascular resistance. As a starting point, the evidence that the Na electrochemical gradient across the vascular smooth muscle cell plasma membrane (sarcolemma) plays an important role in cell calcium regulation is reviewed. Because there is significant resting tension ("tone") in most resistance vessels, the ionized Ca2+ level ([Ca2+]1) in the smooth muscle fibers in these vessels must be maintained above the contraction threshold. Consequently, the Ca transport system in the sarcolemma, presumably an Na-Ca exchange mechanism, must be set so as to hold [Ca2+]1 at this suprathreshold level. Any change in the Na gradient will then be reflected as a change in [Ca2+]1 and, therefore, in steady vessel wall tension and peripheral resistance. The correlation between Na metabolism and hypertension could then be accounted for if a circulating agent, perhaps the "natriuretic hormone," affects the Na gradient (across the sarcolemma) and, therefore, [Ca2+]1 and tension.     

Cholinergic-adrenergic interactions on intestinal ion transport.

The autonomic control of intestinal electrolyte transport has been investigated in the in vitro, short-circuited rabbit ileum with varying doses of carbachol and with neuroeffector blocking agents. Low-dose carbachol (less than 10(-6) M) and high-dose carbachol (greater than 10(-4) M) had different effects on Na and Cl transport. Low-dose carbachol caused a transient increase in the potential difference and short-circult current, stimulated Cl secretion, and inhibited the residual flux (probably HCO3 secretion). This is a muscarinic response since it is inhibited by atropine (10(-6) M). After an initial increase of the potential difference and short-circuit current, high-dose carbachol reduced these electrical parameters, stimulated Na and Cl absorption, and abolished the residual flux. This is a nicotinic response since it is inhibited by hexamethonium (10(-5) M). This nicotinic response is identical to that reported by others with alpha-adrenergic agents and it was inhibited also by phentolamine (10(-7) M). We propose that high-dose carbachol stimulates nicotinic receptors on postganglionic sympathetic fibers present in our preparations causing a release of catecholamines and a resulting alpha-adrenergic response by the intestinal epithelial cell. The physiological significance of this response in the gut remains to be determined.     

Effects of training on potassium,calcium and hydrogen ion regulation in skeletal muscle and blood during exercise

Ionic regulation is critical to muscle excitation, contraction and metabolism, and thus for muscle function during exercise. This review focuses on the effects of training upon K⁺, Ca²⁺ and H⁺ ion regulation in muscle and K⁺ regulation in blood during exercise. Training enhances K⁺ regulation in muscle and blood and reduces muscular fatiguability. Endurance, sprint and strength training in humans induce an increased muscle Na⁺, K⁺ pump concentration, usually associated with a reduced rise in plasma [K⁺] during exercise. Although impaired muscle Ca²⁺ regulation plays a vital role in fatigue, little is known about possible training effects. In rat fast-twitch muscle, overload-induced hypertrophy and endurance training were associated with reduced sarcoplasmic reticulum Ca²⁺ uptake, consistent with fast-to-slow fibre transition. In human muscle, endurance and strength training had no effect on muscle Ca²⁺ ATPase concentration. Whilst muscle Ca²⁺ uptake, release and Ca²⁺ ATPase activity were depressed by fatigue, no differences were found between strength athletes and untrained individuals. Muscle H⁺ accumulation may contribute to fatigue during intense exercise and is also modified by sprint training. Sprint training may increase muscle Lac^- and work output with exhaustive exercise, but the rise in muscle [H⁺] is unchanged or attenuated, indicating a reduced rise in muscle [H⁺] relative to work performed. Muscle buffering capacity can be dissociated from this improved H⁺ regulatory capacity after training. Thus, training enhances muscle and blood K⁺ and muscle H⁺ regulation during exercise, consistent with improved muscular performance and reduced fatiguability; however, little is known about training effects on muscle Ca²⁺ regulation during contraction.     

Therapeutic modulation of microbiota-host metabolic interactions

The complex metabolic relationships between the host and its microbiota change throughout life and vary extensively between individuals, affecting disease risk factors and therapeutic responses through drug metabolism. Elucidating the biochemical mechanisms underlying this human supraorganism symbiosis is yielding new therapeutic insights to improve human health, treat disease, and potentially modify human disease risk factors. Therapeutic options include targeting drugs to microbial genes or co-regulated host pathways and modifying the gut microbiota through diet, probiotic and prebiotic interventions, bariatric surgery, fecal transplants, or ecological engineering. The age-associated co-development of the host and its microbiota provides a series of windows for therapeutic intervention from early life through old age.     

Sodium/calcium exchange in tonic skeletal muscle fibers of the frog.

The Na/Ca exchange system was investigated by contractile response to alteration of the extracellular sodium concentration in tonic skeletal muscle fibers of the frog. Contractures were evoked when the extracellular sodium was reduced or withdrawn in the normal solution. This effect was not associated with membrane depolarizations. In the presence of d-tubocurarine, the amplitude and time course of sodium withdrawal contractures were modified, except when sodium was replaced by TEA. When external calcium was omitted from the solution, the tension of sodium withdrawal contracture was greatly reduced. This effect was reversible. These results suggest that Na/Ca exchange is present in the membrane of tonic skeletal muscle fibers of the frog. This conclusion is further supported by the effect of veratridine and strophantidin, which increase the tension of the low-sodium contractures.