Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Excessive Ca(2+) can be detrimental to cells and raised levels of Ca(2+) in human lenses with cortical cataract have been found to play a major role in the opacification process. Ca(2+) homeostasis is therefore, recognised as having fundamental importance in lens pathophysiology. Furthermore, Ca(2+) plays a central role as a second messenger in cell signalling and mechanisms have evolved which give cells exquisite control over intracellular Ca(2+) ([Ca(2+)](i)) via an array of specialised regulatory and signalling proteins. In this review we discuss these mechanisms as they apply to the lens. Ca(2+) levels in human aqueous humour are approximately 1 mM and there is a large, 10,000 fold, inwardly directed gradient across the plasma membrane. In the face of such a large gradient highly efficient mechanisms are needed to maintain low [Ca(2+)](i). The Na(+)/Ca(2+) exchanger (NCX) and plasma membrane Ca(2+)-ATPase (PMCA) actively remove Ca(2+) from the cells, whereas the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) sequesters Ca(2+) in the endoplasmic reticulum (ER) Ca(2+) store. In lens epithelial cells the dominant role is played by the ATPases, whilst in the fibre cells NCX activity appears to be more important. Usually, [Ca(2+)](i) can be increased in a number of ways. Ca(2+) influx through the plasma membrane, for example, is mediated by an array of channels with evidence in the lens for the presence of voltage-operated Ca(2+) channels (VOCCs), receptor-operated Ca(2+) channels (ROCCs) and channels mediating store-operated Ca(2+) entry (SOCE). Ca(2+) signalling is initiated via activation of G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTK) of which the lens expresses a surprisingly diverse array responding to various neurotransmitters, hormones, growth factors, autocoids and proteases. Downstream of plasma membrane receptors are IP(3)-gated channels (IP(3)Rs) and ryanodine receptors (RYRs) located in the ER, which when activated cause a rapid increase in [Ca(2+)](i) and these have also been identified in the lens. Through an appreciation of the diversity and complexity of the mechanisms involved in Ca(2+) homeostasis in normal lens cells we move closer to an understanding of the mechanisms which mediate pathological Ca(2+) overload as occurs in the process of cataract formation.
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PMID:The mechanisms of calcium homeostasis and signalling in the lens. 1906 88

An adverse environmental experience of the growing fetus leads to permanent changes in the structure and contractile function of the heart; however, the mechanisms are incompletely understood. To examine if a maternal low protein (LP) diet can modulate the gene and protein expression of the Ca(2+)-cycling proteins in the neonatal heart, we employed a rat model in which pregnant dams were fed diets containing either 180 (normal) or 90 g (low) casein/kg diet for 2 weeks before mating and throughout pregnancy. A significant reduction in the L-type Ca(2+)-channel mRNA level in the LP group was detected at 1, 7, and 14 days of age. Although ryanodine receptor (RyR) mRNA levels progressively declined in the aging heart in both groups, the RyR mRNA levels were consistently higher in the LP group. A reduction in RyR protein content was seen only in the hearts of the LP group at 7 days of age. The Na(+)-Ca(2+)-exchanger (NCX) mRNA level was also markedly increased at all ages. Although an increase in sarco(endo)plasmic reticulum ATPase 2a (SERCA) 2a mRNA was only detected in the LP group at 7 days of age, corresponding protein level was depressed. On the other hand, an initial decrease (at 1 day of age) followed by an increase (at 14 and 28 days of age) in phospholamban (PLB) mRNA levels was detected. Although PLB protein level was also depressed at 1 day of age in the LP group, a marked increase was seen at 7 days of age. Moreover, the ratio of serine 16 and threonine 17 phosphorylated PLB to non-phosphorylated PLB was reduced at 7 days of age in the hearts of offspring of the LP group. These data suggest that maternal LP diet can induce alterations in the gene expression and protein levels of the Ca(2+)-cycling proteins in the neonatal heart.
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PMID:Alterations in the expression of myocardial calcium cycling genes in rats fed a low protein diet in utero. 1910 11

Intracellular Na(+) concentration ([Na(+)](i)) is very important in modulating the contractile and electrical activity of the heart. Upon electrical excitation of the myocardium, voltage-dependent Na(+) channels open, triggering the upstroke of the action potential (AP). During the AP, Ca(2+) enters the myocytes via L-type Ca(2+) channels. This triggers Ca(2+) release from the sarcoplasmic reticulum (SR) and thus activates contraction. Relaxation occurs when cytosolic Ca(2+) declines, mainly due to re-uptake into the SR via SR Ca(2+)-ATPase and extrusion from the cell via the Na(+)/Ca(2+) exchanger (NCX). NCX extrudes one Ca(2+) ion in exchange for three Na(+) ions and its activity is critically regulated by [Na(+)](i). Thus, via NCX, [Na(+)](i) is centrally involved in the regulation of intracellular [Ca(2+)] and contractility. Na(+) brought in by Na(+) channels, NCX and other Na(+) entry pathways is extruded by the Na(+)/K(+) pump (NKA) to keep [Na(+)](i) low. NKA is regulated by phospholemman, a small sarcolemmal protein that associates with NKA. Unphosphorylated phospholemman inhibits NKA by decreasing the pump affinity for internal Na(+) and this inhibition is relieved upon phosphorylation. Here we discuss the main characteristics of the Na(+) transport pathways in cardiac myocytes and their physiological and pathophysiological relevance.
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PMID:Na+ transport in cardiac myocytes; Implications for excitation-contraction coupling. 1924 7

Extracellular ATP (eATP) induces an intracellular Ca(2+) transient by activating phospholipase C (PLC)-associated P2X4 purinergic receptors, leading to production of inositol 1,4,5-trisphosphate (IP3) and subsequent Ca(2+) release from intracellular stores in mouse pancreatic beta-cells. Using laser scanning confocal microscopy, Ca(2+) indicator fluo-4 AM, and the cell permeable nuclear indicator Hoechst 33342, we examined the properties of eATP-induced Ca(2+) release in pancreatic beta-cell nuclei. eATP induced a higher nuclear Ca(2+) transient in pancreatic beta-cell nuclei than in the cytosol. After pretreatment with thapsigargin (TG), an inhibitor of sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) pumps, the amplitude of eATP-induced Ca(2+) transients in the nucleus was still much higher than those in the cytosol. This effect of eATP was not altered by inhibition of either the plasma membrane Ca(2+)-ATPase (PMCA) or the plasma membrane Na(+)/Ca(2+) exchanger (NCX) by LaCl(3) or by replacement of Na(+) with N-Methyl-Glucosamine. eATP-induced nuclear Ca(2+) transients were abolished by a cell-permeable IP3R inhibitor, 2-aminoethoxydiphenyl borate (2-APB), but were not blocked by the ryanodine receptor (RyR) antagonist ryanodine. Immunofluorescence studies showed that IP3Rs are expressed on the nuclear envelope of pancreatic beta-cells. These results indicate that eATP triggers nuclear Ca(2+) transients by mobilizing a nuclear Ca(2+) store via nuclear IP3Rs.
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PMID:Extracellular ATP-induced nuclear Ca2+ transient is mediated by inositol 1,4,5-trisphosphate receptors in mouse pancreatic beta-cells. 1928 37

We hypothesized that testosterone at physiological levels enhances cardiac contractile responses to stimulation of both alpha(1)- and beta(1)-adrenoceptors by increasing Ca(2+) release from the sarcoplasmic reticulum (SR) and speedier removal of Ca(2+) from cytosol via Ca(2+)-regulatory proteins. We first determined the left ventricular developed pressure, velocity of contraction and relaxation, and heart rate in perfused hearts isolated from control rats, orchiectomized rats, and orchiectomized rats without and with testosterone replacement (200 microg/100 g body wt) in the presence of norepinephrine (10(-7) M), the alpha(1)-adrenoceptor agonist phenylephrine (10(-6) M), or the nonselective beta-adrenoceptor agonist isoprenaline (10(-7) M) in the presence of 5 x 10(-7) M ICI-118,551, a beta(2)-adrenoceptor antagonist. Next, we determined the amplitudes of intracellular Ca(2+) concentration transients induced by electrical stimulation or caffeine, which represent, respectively, Ca(2+) release via the ryanodine receptor (RyR) or releasable Ca(2+) in the SR, in ventricular myocytes isolated from the three groups of rats. We also measured (45)Ca(2+) release via the RyR. We then determined the time to 50% decay of both transients, which represents, respectively, Ca(2+) reuptake by sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) and removal via the sarcolemmal Na(+)/Ca(2+) exchanger (NCX). We correlated Ca(2+) removal from the cytosol with activities of SERCA and its regulator phospholamban as well as NCX. The results showed that testosterone at physiological levels enhanced positive inotropic and lusitropic responses to stimulation of alpha(1)- and beta(1)-adrenoceptors via the androgen receptor. The increased contractility and speedier relaxation were associated with increased Ca(2+) release via the RyR and faster Ca(2+) removal out of the cytosol via SERCA and NCX.
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PMID:Testosterone-augmented contractile responses to alpha1- and beta1-adrenoceptor stimulation are associated with increased activities of RyR, SERCA, and NCX in the heart. 1933 23

The goal of our study was to evaluate the origin of the increased O(2) consumption in electrically stimulated left ventricular slices of isoproterenol-induced hypertrophied rat hearts with normal left ventricular pressure. O(2) consumption per minute (mVO(2)) of mechanically unloaded left ventricular slices was measured in the absence and presence of 1-Hz field stimulation. Basal metabolic mVO(2), i.e., mVO(2) without electrical stimulation, was significantly smaller, but mVO(2) for the total Ca(2+) handling in excitation-contraction coupling (E-C coupling mVO(2)), i.e., delta mVO(2) (=mVO(2) with stimulation - mVO(2) without stimulation), was significantly larger in the hypertrophied heart. Furthermore, the fraction of E-C coupling mVO(2) was markedly altered in the hypertrophied heart. Namely, mVO(2) consumed by sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2) was depressed by 40%; mVO(2) consumed by the Na(+)/K(+)-ATPase (NKA)-Na(+)/Ca(2+) exchange (NCX) coupling was increased by 100%. The depressed mVO(2) consumption by SERCA2 was supported by lower protein expressions of phosphorylated-Ser(16) phospholamban and SERCA2. The increase in NKA-NCX coupling mVO(2) was supported by marked augmentation of NCX current. However, the increase in NCX current was not due to the increase in NCX1 protein expression, but was attributable to attenuation of the intrinsic inactivation mechanisms. The present results demonstrated that the altered origin of the increased E-C coupling mVO(2) in hypertrophy was derived from decreased SERCA2 activity (1ATP: 2Ca(2+)) and increased NCX activity coupled to NKA activity (1ATP: Ca(2+)). Taken together, we conclude that the energetically less efficient Ca(2+) extrusion pathway evenly contributes to Ca(2+) handling in E-C coupling in the present hypertrophy model.
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PMID:Increased O2 consumption in excitation-contraction coupling in hypertrophied rat heart slices related to increased Na+ -Ca2+ exchange activity. 1934 May 63

Closure of the ductus arteriosus (DA) after birth, essential for postnatal adaptation, is initiated by the transition from hypoxia to normoxia. The current study investigated how hypoxia affects the level of cytosolic calcium ([Ca(2+)](i)) in fetal lamb DA smooth muscle cells (DASMCs) and the role of calcium pumps in this process. The [Ca(2+)](i) variation in response to acute hypoxia was determined spectrofluorometrically with fura-3-AM in cultured fetal DASMCs. Interventions using chemicals or solutions including thapsigargin, vanadate, KB-R7943, alkaline PH9.0 solution, or Na(+)-free medium were administered when samples were exposed to acute hypoxia. The results show that [Ca(2+)](i) decreased dramatically under acute hypoxia. This decrease was not attenuated completely by an inhibitor of sarcoplasmic/endoplasmic reticulum Ca(2+) adenosine triphosphatase (ATPase) (SERCA), a blocker of plasma membrane Ca(2+) ATPase (PMCA), or an inhibitor and activator of the reserve mode of the Na(+)/Ca(2+) exchanger (NCX). In contrast, KT-R9743, an inhibitor of the forward mode of NCX at a high concentration (30 microm), greatly diminished the hypoxia-induced [Ca(2+)](i) decrease in fetal DASMCs. These results suggest that a hypoxia-induced Ca(2+) decrease in fetal DASMCs results from cytosolic Ca(2+) efflux mediated primarily by the forward mode of NCX.
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PMID:Hypoxia-induced cytosolic calcium decrease is mediated primarily by the forward mode of Na(+)/Ca(2+) exchanger in smooth muscle cells of fetal ductus arteriosus. 1949 47

In mammalian adult cardiomyocytes, sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA) plays a major role in controlling the decline of cytosolic free Ca(2+) concentration ([Ca(2+)](i)) in comparison with sarcolemmal Na(+)/Ca(2+) exchanger (NCX). However, the functional importance of SERCA and NCX in cytosolic Ca(2+) removal during early cardiomyogenesis is still debated. In this study, the functional contributions of Ca(2+) transporters to [Ca(2+)](i) decline in mouse embryonic stem cell-derived cardiomyocytes (mESCMs), a suitable model for investigation of early cardiogenesis, at various differentiation stages were investigated. We estimated that even at early differentiation stages of mESCMs, SERCA was responsible for approximately 76% of total Ca(2+) removal, while NCX was responsible for approximately 21%. The contributions of SERCA and NCX to cytosolic Ca(2+) clearance were increased to approximately 88% and decreased to approximately 10%, respectively, at the late differentiation stage. Dynamical analysis of the transient decay phases in normal and Na(+)-free solutions suggests that the contribution of NCX to [Ca(2+)](i) decline is more apparent in the terminal slow decay phase than that in the initial fast phase. When SR function was suppressed in type 2 ryanodine receptor-null mESCMs or with ryanodine receptor and SERCA inhibitors (ryanodine and thapsigargin), NCX acted as the main pathway for [Ca(2+)](i) decline. We conclude that the rapid [Ca(2+)](i) decline is mainly achieved by the SR uptake even at the early differentiation stage of mESCMs, while NCX acts as the main Ca(2+) remover when SR function is suppressed. These findings suggest a critical role of SR in the regulation of [Ca(2+)](i) homeostasis even in differentiating cardiomyocytes.
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PMID:Ca2+ removal mechanisms in mouse embryonic stem cell-derived cardiomyocytes. 1960 39

A brief historical background on synaptic transmission in relation to Ca(2+) dynamics and short-term facilitation is described. This study focuses on the mechanisms responsible for the regulation of intracellular calcium concentration ([Ca(2+)](i)) in high output terminals of larval Drosophila compared to a low-output terminal of the crayfish neuromuscular junction (NMJ). Three processes; plasmalemmal Na(+)/Ca(2+) exchanger [NCX], Ca(2+)-ATPase (PMCA), and sarcoplasmic/endoplasmic Ca(2+)-ATPase (SERCA) are important in regulating the [Ca(2+)](i) are examined. When the NCX is compromised by reduced [Na(+)](o), no consistent effect occurred; but a NCX blocker KB-R7943 decreased the excitatory postsynaptic potential (EPSP) amplitudes. Compromising the PMCA with pH 8.8 resulted in an increase in EPSP amplitude but treatment with a PMCA specific inhibitor carboxyeosin produced opposite results. Thapsigargin exposure to block the SERCA generally decreases EPSP amplitude. Compromising the activity of the above Ca(2+) regulating proteins had no substantial effects on short-term depression. The Kum(170TS) strain (with dysfunctional SERCA), showed a decrease in EPSP amplitudes including the first EPSP within the train. Synaptic transmission is altered by reducing the function of the above three [Ca(2+)](i) regulators; but they are not consistent among different species as expected. Results in crayfish NMJ were more consistent with expected results as compared to the Drosophila NMJ. It is predicated that different mechanisms are used for regulating the [Ca(2+)](i) in high and low output synaptic terminals.
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PMID:Different mechanisms of Ca2+ regulation that influence synaptic transmission: comparison between crayfish and Drosophila neuromuscular junctions. 1965 Jan 16

We present a stochastic computational model to study the mechanism of signaling between a source and a target ionic transporter, both localized on the plasma membrane (PM). In general this requires a nanometer-scale cytoplasmic space, or nanodomain, between the PM and a peripheral organelle to reflect ions back towards the PM. Specifically we investigate the coupling between Na(+) entry via the transient receptor potential canonical channel 6 (TRPC6) and the Na(+)/Ca(2+) exchanger (NCX), a process which is essential for reloading the sarcoplasmic reticulum (SR) via the sarco/endoplasmic reticulum Ca(2+)ATPase (SERCA) and maintaining Ca(2+) oscillations in activated vascular smooth muscle. Having previously modeled the flow of Ca(2+) between reverse NCX and SERCA during SR refilling, this quantitative approach now allows us to model the upstream linkage of Na(+) entry through TRPC6 to reversal of NCX. We have implemented a random walk (RW) Monte Carlo (MC) model with simulations mimicking a diffusion process originating at the TRPC6 within PM-SR junctions. The model calculates the average Na(+) in the nanospace and also produces profiles as a function of distance from the source. Our results highlight the necessity of a strategic juxtaposition of the relevant ion translocators as well as other physical structures within the nanospaces to permit adequate Na(+) build-up to initiate NCX reversal and Ca(2+) influx to refill the SR.
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PMID:A model for the generation of localized transient [Na+] elevations in vascular smooth muscle. 1973 53


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