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)

Earlier studies have shown that the efferent ductules (ED) of the male mouse are a target for estrogen. The loss of estrogen receptor (ER) function through either knockout technology (alpha ERKO mouse) or chemical interference (pure antagonist, ICI 182 780) results in a failure of a major function of the ED, the reabsorption of testicular fluids. The purpose of this study was to test the hypothesis that estrogen controls fluid (water) reabsorption in the ED by modulating ion transporters important for passive water movement through a leaky epithelium such as the ED. Northern blot analysis was used to detect the mRNA levels for key ion transporters in the following experimental groups: 1) wild-type (WT) control for the 14-day experiment, 2) ER alpha knockout (alpha ERKO) control for the 14-day experiment, 3) WT treated with ICI 182 780 (ICI) for 14 days, 4) alpha ERKO treated with ICI for 14 days, 5) WT control for the 35-day experiment, and 6) WT treated with ICI for 35 days. Estrogen differentially modulated the mRNA levels of key ion transporters. ER alpha mediated carbonic anhydrase II mRNA abundance, and there was a decrease in Na(+)/H(+) exchanger 3 mRNA levels in the alpha ERKO that appeared to be a cellular effect and not a direct estrogen effect. The loss of ER alpha control resulted in an increase in mRNA abundance for the catalytic subunit of Na(+)-K(+) ATPase alpha 1, whereas an increase in the mRNA abundance of the Cl(-)/HCO(3)(-) exchanger and the chloride channel cystic fibrosis transmembrane regulator was significantly ER beta mediated. Our results indicate for the first time that estrogen acting directly and indirectly through both ER alpha and ER beta probably modulates fluid reabsorption in the adult mouse ED by regulating the expression of ion transporters involved in the movement of Na(+) and Cl(-).
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PMID:Estrogen regulation of ion transporter messenger RNA levels in mouse efferent ductules are mediated differentially through estrogen receptor (ER) alpha and ER beta. 1167 72

Vacuolar type H(+)-ATPase is involved in lumenal acidification of the epididymis. This protein is highly expressed in narrow and clear cells where it is located in the apical pole, and it contributes to proton secretion into the lumen. We have previously shown that in rats, epididymal cells rich in H(+)ATPase appear during postnatal development and reach maximal numbers at 3-4 wk of age. The factors that regulate the appearance of these cells have not been investigated, but androgens, estrogens, or both may be involved. This study examined whether neonatal administration of estrogens (diethylstilbestrol [DES] or ethinyl estradiol) or an antiandrogen (flutamide), or the suppression of androgen production via administration of a GnRH antagonist (GnRHa), was able to alter the appearance of cells rich in H(+)-ATPase in the rat epididymis when assessed at age 25 days. Surprisingly, all of these treatments were able to significantly reduce the number of H(+)-ATPase positive cells; this was determined by immunofluorescence and confirmed by Western blotting. In contrast, neonatal coadministration of DES and testosterone maintained the expression of H(+)-ATPase in the epididymis at Day 25 despite the high level of concomitant estrogen exposure. These findings indicate that androgens, acting via the androgen receptor, are essential for the normal development of epididymal cells rich in H(+)-ATPase, and that treatments that interfere directly or indirectly with androgen production (GnRHa, DES) or action (flutamide, DES) will result in reduced expression of H(+)-ATPase. Our findings do not exclude the possibility that estrogens can directly suppress the postnatal development of cells in the epididymis that are rich in H(+)-ATPase, but if this is the case, this suppression can be prevented by testosterone administration.
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PMID:Modulation of the onset of postnatal development of H(+)-ATPase-rich cells by steroid hormones in rat epididymis. 1229 25

Estrogen status is known to affect the incidence of cardiovascular disease. Experiments were designed to prove the influences of in vivo estrogen manipulations on vascular hyperpolarization and relaxation mediated by endothelium-derived hyperpolarizing factor (EDHF), and to explore the possible mechanism contributing to the altered EDHF responses in estrogen-deficient states. Mesenteric arteries with intact endothelium were isolated from sham-operated (control), ovariectomized (OVX), or OVX with 17beta-estradiol replacement (OVX + E ) female rats. In the presence of apamin and charybdotoxin, there was no difference between groups in relaxations to the Ca ionophore A23187 and the endoplasmic reticulum Ca -adenosine triphosphatase inhibitor cyclopiazonic acid (CPA). However, N -nitro-L-arginine produced a marked decrease in A23187- and CPA-induced relaxations in OVX compared with control and OVX + E arteries. In control arteries, A23187 and CPA elicited membrane hyperpolarization in a sustained manner. In contrast, A23187 produced only a small and transient hyperpolarizing effect in OVX arteries. OVX also greatly attenuated the sustained pattern of hyperpolarization to CPA. Such changes in hyperpolarizations were not seen in OVX + E arteries. The EDHF-mediated relaxant and hyperpolarizing responses of control arteries to A23187 and CPA were significantly inhibited by the gap junction inhibitor 18 alpha-glycyrrhetinic acid. Immunohistochemical examination for connexin-43 showed that the expression was abundant along the endothelial layer in control and OVX + E arteries, while being much less in OVX arteries. It was concluded that estrogen deficiency specifically impairs EDHF-mediated vascular actions. This may be partly explained by the reduced expression of connexin-43, a protein molecule that could form myoendothelial gap junction channels.
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PMID:Ovariectomy attenuates hyperpolarization and relaxation mediated by endothelium-derived hyperpolarizing factor in female rat mesenteric artery: a concomitant decrease in connexin-43 expression. 1245 28

We previously reported that 17beta-estradiol (betaE2) inhibits the rise in [Ca(2+)](i) and [Na(+)](i) during metabolic inhibition (MI) in mouse cardiomyocytes, but the mechanism has not yet been clarified. Estrogen has been reported to have anti-oxidant properties. We, therefore, have investigated whether interaction with the estrogen receptor (ER) is involved, or whether estrogen reduces free-radical-induced impairment of Na(+)-K(+) ATPase in cardiac myocytes, and whether this effect reduces [Ca(2+)](i) rise. Male mouse ventricular myocytes were studied. Flow cytometry was used with fluo-3 for [Ca(2+)](i) measurement. Dead cells were excluded from analysis by propidium iodide fluorescence. betaE2 reduced the increase in [Ca(2+)](i) during MI even in the presence of the ER blocker tamoxifen. A similar effect on [Ca(2+)](i) was produced by its non-estrogenic isomer, betaE2-estradiol. Other hormones (estrone and estriol) with a phenolic structure also inhibited Ca(2+) overload during MI, but testosterone without the structure did not. The betaE2 effect was attenuated by inhibition of Na(+)-Ca(2+) exchanger (KB-R7943) or Na(+)-K(+) ATPase (low K(+) or ouabain), but not by block of L-type Ca(2+) channel (nifedipine). Tiron (4,5-dihydroxy-1,3-benzenedisulfonic acid), a superoxide scavenger, decreased the rise in [Ca(2+)](i) and abolished the betaE2 effect during MI. We conclude that the acute cardioprotective effect of estrogen during MI may be mediated by an ER-independent anti-oxidant action, which results in improved function of Na(+)-K(+) ATPase.
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PMID:Anti-oxidant effects of estrogen reduce [Ca2+]i during metabolic inhibition. 1267 48

Neuron viability and defense against neurodegenerative disease can be achieved by targeting mitochondrial function to reduce oxidative stress, increase mitochondrial defense mechanisms, or promote energetic metabolism and Ca2+ homeostasis. Exposure to estrogen prior to contact with toxic agents can protect neurons against a wide range of degenerative insults. The proactive defense state induced by estrogen is mediated by complex mechanisms ranging from chemical to biochemical to genomic but which converge upon regulation of mitochondria function. Estrogen preserves ATP levels via increased/enhanced oxidative phosphorylation and reduced ATPase activity thereby increasing mitochondrial respiration efficiency, resulting in a lower oxidative load. In addition, estrogen increases antiapoptotic proteins, Bcl-2 and Bcl-xL, which prevents activation of the permeability transition pore protecting against estrogen-induced increase in mitochondrial Ca2+ sequestration. These effects are likely to be enhanced by antioxidant effects of estrogen, preventing the initiation of the deleterious "mitochondrial spiral". The extent to which each of these mechanisms contribute to the overall proactive defense state induced by estrogen remains to be determined. However, each aspect of the cascade appears to make a significant if not obligatory impact on the neuroprotective effects of estrogens. Moreover each component of the cascade is required for estrogen regulation of mitochondrial function. Mechanisms of estrogen action and results of the clinical efficacy of estrogen therapy for prevention or treatment of Alzheimer's disease are considered in the context of clinical use of estrogen therapy and the design of brain selective estrogens or NeuroSERMs.
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PMID:Mitochondria as therapeutic targets of estrogen action in the central nervous system. 1537 6

Regulation of cellular Ca(2+) cycling is central to myocardial contractile function. Loss of Ca(2+) regulation is associated with cardiac dysfunction and pathology. Estrogen has been shown to modify contractile function and to confer cardioprotection. Therefore, we investigated the effect of estrogen on expression of rat heart myocardial Ca(2+)-handling proteins and beta-adrenergic receptor (beta(1)-AR) and examined functional correlates. Female rats were sham-operated (SHAM) or ovariectomized. Two weeks after ovariectomy rats were injected (i.p.) daily with estradiol benozoate (OVX+EB) or sesame oil (OVX) for 2 weeks. Protein abundance was measured by immunoblotting and mRNA was quantified by real-time RT-PCR. OVX significantly decreased estrogen and progesterone levels and EB replacement returned both estrogen and progesterone to physiological levels. OVX induced a 75% reduction of uterine weight and a gain in body weight. Replacement restored weights to SHAM level. OVX increased and estrogen-replacement normalized abundance of beta(1)-AR and L-type Ca(2+) channel (Cav1.2) protein. OVX decreased sodium-Ca(2+) exchange protein (NCX) and estrogen restored protein abundance to SHAM levels. Sarcoplasmic reticular ATPase (SERCA), phospholamban (PLB), and ryanodine receptor (RyR) abundance was not altered by hormone status. Levels of mRNA encoding for beta(1)-AR, Cav1.2, and NCX were not influenced by OVX or estrogen replacement. OVX had no effect on SERCA and PLB mRNA level but estrogen replacement elicited a significant increase compared to OVX and SHAM. Estrogen-dependent changes in Ca(2+)-handling proteins and beta(1)-AR are theoretically consistent reduced myocellular Ca(2+) load. However, hormone-dependent alterations in protein were not associated with changes in contractile function.
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PMID:Effect of estrogen on calcium-handling proteins, beta-adrenergic receptors, and function in rat heart. 1664 22

Estrogen modulates tight junctional resistance through estrogen receptor-alpha-mediated remodeling of occludin. The objective of the study was to understand the mechanisms involved. Experiments using human normal vaginal-cervical epithelial cells showed that human normal vaginal-cervical epithelial cells secrete constitutively matrix-metalloproteinase-7 (MMP-7) into the luminal solution and that MMP-7 is necessary and sufficient to produce estrogen decrease of tight junctional resistance and remodeling of occludin. Treatment with estrogen stimulated activation of the pro-MMP-7 intracellularly and augmented secretion of the activated MMP-7 form. Steady-state levels of MMP-7 mRNA and protein were not affected by estrogen. Estrogen modulated phosphorylation of the MMP-7, but the changes were most likely secondary to changes in cellular MMP-7 mass. Estrogen increased coimmunoreactivity of MMP-7 with the Golgi protein GPP130. Tunicamycin and brefeldin-A had no effect on cellular MMP-7 but monensin (inhibitor of Golgi traffic) blocked estrogen effects, suggesting estrogen site of action is at the Golgi system. Estrogen increased generalized secretory activity, including of luminal exocytosis of polycarbohydrates. However, estrogen increased coimmunoreactivity of MMP-7 with synaptosomal-associated protein of 25 kDa in apical membranes, suggesting soluble N-ethylmaleimide sensitive fusion factor attachment protein receptor-facilitated exocytosis of MMP-7. Treatment with the vesicular-ATPase inhibitor bafilomycin A(1) inhibited activation of MMP-7. These data suggest that estrogen up-regulates activation of the MMP-7 intracellularly, at the level of Golgi, and augments secretion of activated MMP-7 through soluble N-ethylmaleimide sensitive fusion factor attachment protein receptor-dependent exocytosis. On the other hand, estrogen acidification of the luminal solution would tend to alkalinize exocytotic vesicles and may lead to decreased activation of the MMP-7. These mechanisms acting in concert could be important for regulation and control of estrogen modulation of paracellular permeability in vivo.
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PMID:Estrogen decrease in tight junctional resistance involves matrix-metalloproteinase-7-mediated remodeling of occludin. 1703 51

Administration of ethinyl estradiol (EE), a widely used component of oral contraceptives, has been associated with impairment of bile flow and the capacity to excrete organic anions in man and experimental animals. alpha-Asarone (2,4,5-trimethoxypropenylbenzene) and 2-methoxy-4-(2-propenyl) phenoxyacetic acid (MPPA) have shown hypolipidemic effects. In addition to these effects, we decided to evaluate the properties of these compounds on EE-induced cholestasis. Wistar male rats were injected subcutaneously with 10 mg/kg of EE for 5 days; simultaneously, alpha-asarone or MPPA were also administered and appropriate controls were performed. alpha-asarone and MPPA decreased plasma and bile cholesterol. EE diminished triglycerides total, low-density lipoprotein, high-density lipoprotein and bile cholesterol. MPPA further decreased these lipid parameters. Alkaline phosphatase (an enzyme marker of cholestasis) was increased after administration of EE, but this effect was prevented significantly by alpha-asarone or MPPA administration. Bile flow was importantly decreased by EE and increased by alpha-asarone alone. Furthermore, alpha-asarone or MPPA preserved the normal bile flow in EE-treated rats. EE inhibited the activity of the Na(+)/K(+)-ATPase, while both alpha-asarone and MPPA preserved this enzyme activity. Na(+)/K(+)-ATPase is involved in Na(+)-coupled uptake of bile acids into hepatocytes and, therefore, ultimately is the driving force for the generation of bile flow. Therefore, the anticholestatic effects of alpha-asarone and MPPA, described herein by the first time, may be due to its ability to preserve ATPase activity. This enzyme is negatively regulated by membrane cholesterol, thus the hypolipidemic effects of the compounds tested may be responsible for Na(+)/K(+)-ATPase activity and bile flow maintenance.
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PMID:Effect of alpha-asarone and a derivative on lipids, bile flow and Na+/K+-ATPase in ethinyl estradiol-induced cholestasis in the rat. 1722 48

Nonylphenol (NP) is the most critical metabolite of alkylphenol polyethoxylate detergents. NP is known as an endocrine disruptor with estrogenic activities and as an inhibitor of endoplasmic reticulum Ca(2+)-ATPase. Estrogen has modulatory roles on ligand-gated ion channels, such as nicotinic acetylcholine receptors (nAChRs). Ca(2+)-ATPase inhibitors can modulate the cytosolic calcium concentration ([Ca(2+)](c)]) and thus can affect the calcium signaling coupled with nAChRs. Therefore, NP is predicted to have complex effects on the Ca(2+) signaling and secretion coupled with nAChRs. This study investigated these effects using bovine adrenal chromaffin cells. The results show that NP suppressed the Ca(2+) signaling coupled with nAChRs and voltage-operated Ca(2+) channels in a dose-dependent manner, with IC(50)s of 1 and 5.9 microM, respectively. Estradiol exhibits similar suppression but much lower inhibitory potencies. NP alone induced a transient rise in [Ca(2+)](c) in the presence or absence of extracellular calcium. Thapsigargin, an endoplasmic reticulum Ca(2+)-ATPase inhibitor, partially suppressed the [Ca(2+)](c) rise induced by NP, but NP totally blocked the [Ca(2+)](c) rise induced by thapsigargin. This illustrates that NP can cause Ca(2+) release from thapsigargin-insensitive pools. Thapsigargin suppressed the Ca(2+) signaling coupled with nAChRs but increased that coupled with voltage-operated Ca(2+) channels. We propose that three routes are responsible for the effects of NP on nAChRs: named receptor channels, voltage-gated Ca(2+) channels, and Ca(2+)-induced Ca(2+) release. Three routes are related to the characteristics of NP as steroid-like compounds and Ca(2+)-ATPase inhibitor.
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PMID:Effects of nonylphenol on the calcium signal and catecholamine secretion coupled with nicotinic acetylcholine receptors in bovine adrenal chromaffin cells. 1809 14

The potential health impact of pharmaceutical waste is now a growing concern. Contraceptive steroids are prominent environmental contaminants and thus may act as endocrine disruptors. Numerous xenobiotics hamper Sertoli cells junctional communication which is known to participate in spermatogenesis control. This has been associated with male subfertility and testicular cancer. We investigated three contraceptive molecules found in the environment for their potential impact on Sertoli cells gap junction functionality: 17a-ethynylestradiol, medroxyprogesterone acetate and levonorgestrel. Four other non-steroid drugs also found in the environment were included in the study. Communication disruption was analyzed in vitro in murine seminiferous tubules and the 42GPA9 Sertoli cell line. Steroids modulated connexin43 trafficking and impaired junctional communication through rapid effects apparently acting on the cell membrane but not on Cx43 expression. The 4 non-steroid compounds showed no effect. Longer exposure to steroids increased gap junction impairment, which was associated in part with Na/K ATPase internalization. Estrogen receptors (ER) did not appear to be involved in gap junction disruption: Sertoli cells are devoid of ERalpha and only express the cytoplasmic beta isoform. ERbeta localization was not modified by either steroid. The threshold level was surprisingly low, around 10(-16) M. We conclude that steroidal pollutants disrupt Sertoli cells junctional communication in vitro at concentrations that can be found in the environment.
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PMID:Contraceptive steroids from pharmaceutical waste perturbate junctional communication in Sertoli cells. 1977 77


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