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)

Maintenance of ion balance requires that ionoregulatory epithelia modulate ion flux in response to internal or environmental osmotic challenges. We have explored the basis of this functional plasticity in the gills of the euryhaline killifish Fundulus heteroclitus. The expression patterns of several genes encoding ion transport proteins were quantified after transfer from near-isosmotic brackish water [10 parts/thousand (ppt)] to either freshwater (FW) or seawater (SW). Many changes in response to SW transfer were transient. Increased mRNA expression occurred 1 day after transfer for Na(+)-K(+)-ATPase-alpha(1a) (3-fold), Na(+)-K(+)-2Cl(-)-cotransporter 1 (NKCC1) (3-fold), and glucocorticoid receptor (1.3-fold) and was paralleled by elevated Na(+)-K(+)-ATPase activity (2-fold). The transient increase in NKCC1 mRNA expression was followed by a later 2-fold rise in NKCC protein abundance. In contrast to the other genes studied in the present work, mRNA expression of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel generally remained elevated (2-fold) in SW. No change in protein abundance was detected, however, suggesting posttranscriptional regulation. The responses to FW transfer were quite different from those to SW transfer. In particular, FW transfer increased Na(+)-K(+)-ATPase-alpha(1a) mRNA expression and Na(+)-K(+)-ATPase activity to a greater extent than did SW transfer but had no effect on V-type H(+)-ATPase expression, supporting the current suggestion that killifish gills transport Na(+) via Na(+)/H(+) exchange. These findings demonstrate unique patterns of ion transporter expression in killifish gills after salinity transfer and illustrate important mechanisms of functional plasticity in ion-transporting epithelia.
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PMID:Changes in gene expression in gills of the euryhaline killifish Fundulus heteroclitus after abrupt salinity transfer. 1504 50

Topical intranasal application of the antifungal Amphotericin B (AmphoB) has been shown as an effective medical treatment of chronic rhinosinusitis. Because this antibiotic forms channels in lipid membranes, we considered the possibility that it affects the properties and/or cell surface expression of ion channels/pumps, and consequently transepithelial ion transport. Human nasal epithelial cells were exposed apically to AmphoB (50 microM) for 4 h, 5 days (4 h daily), and 4 weeks (4 h daily, 5 days weekly) and allowed to recover for 18-48 h. AmphoB significantly reduced transepithelial potential difference, short-circuit current, and the amiloride-sensitive current. This was not due to generalized cellular toxicity as judged from normal transepithelial resistance and mitochondrial activity, but was related to inhibitory effects of AmphoB on ion transport proteins. Thus, cells exposed to AmphoB for 4 h showed decreased apical epithelial sodium channels (ENaC) activity with no change in basolateral Na(+)K(+)-ATPase activity and K(+) conductance, and reduced amount of alphaENaC, alpha1-Na(+)K(+)-ATPase, and NKCC1 proteins at the cell membrane, but no change in mRNA levels. After a 5-day treatment, there was a significant decrease in Na(+)K(+)-ATPase activity. After a 4-week treatment, a decrease in basolateral K(+) conductance and in alphaENaC and alpha1-Na(+)K(+)-ATPase mRNA levels was also observed. These findings may reflect a feedback mechanism aimed to limit cellular Na(+) overload and K(+) depletion subsequently to formation of AmphoB pores in the cell membrane. Thus, the decreased Na(+) absorption induced by AmphoB resulted from reduced cell surface expression of the ENaC, Na(+)K(+)-ATPase pump and NKCC1 and not from direct inhibition of their activities.
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PMID:Effects of amphotericin B on ion transport proteins in airway epithelial cells. 1579 30

Previous research has suggested that northern populations of the euryhaline killifish (Fundulus heteroclitus) are better adapted to freshwater environments than their southern counterparts. In this study, we examined whether this adaptation has come at an ionoregulatory cost in seawater, by comparing published data for northern killifish to newly acquired data on the molecular responses of southern killifish to seawater transfer. After abrupt transfer from brackish water (10 per thousand) to seawater, Na,K-ATPase activity, Na,K-ATPase alpha(1a) mRNA expression, and NKCC1 mRNA expression increased 1 and 4 days after transfer in the gills of southern fish (by 2-3-fold), but increased at 1 day and not 4 days after transfer in northern fish. Small increases in mRNA expression were observed in both populations at 14 days. CFTR expression also increased in southern and northern fish at 1 and 4 days into seawater, and was also elevated at 14 days in northern fish. Because fish from both southern and northern populations maintained plasma Na(+) and Cl(-) balance after seawater transfer, the differences in activity and expression could not have been caused by differences in plasma ion levels. Instead, some other regulatory factor may account for the differences in expression between populations. This study shows that freshwater adaptation in northern populations of killifish has not necessarily come at a significant ionoregulatory cost in seawater, but has altered the molecular responses of their gills to seawater transfer compared to southern killifish.
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PMID:Intraspecific variation in gene expression after seawater transfer in gills of the euryhaline killifish Fundulus heteroclitus. 1595 46

In secretory epithelia, activation of PKC by phorbol ester and carbachol negatively regulates Cl(-) secretion, the transport event of secretory diarrhea. Previous studies have implicated the basolateral Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) as a target of PKC-dependent inhibition of Cl(-) secretion. In the present study, we examined the regulation of surface expression of NKCC1 in response to the activation of PKC. Treatment of confluent T84 intestinal epithelial cells with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (PMA) reduced the amount of NKCC1 accessible to basolateral surface biotinylation. Loss of cell surface NKCC1 was due to internalization as shown by 1) the resistance of biotinylated NKCC1 to surface biotin stripping after incubation with PMA and 2) indirect immunofluorescent labeling. PMA-induced internalization of NKCC1 is dependent on the epsilon-isoform of PKC as determined on the basis of sensitivity to a panel of PKC inhibitors. The effect of PMA on surface expression of NKCC1 was specific because PMA did not significantly alter the amount of Na(+)-K(+)-ATPase or E-cadherin available for surface biotinylation. After extended PMA exposure (>2 h), NKCC1 became degraded in a proteasome-dependent fashion. Like PMA, carbachol reduced the amount of NKCC1 accessible to basolateral surface biotinylation in a PKC-epsilon-dependent manner. However, long-term exposure to carbachol did not result in degradation of NKCC1; rather, NKCC1 that was internalized after exposure to carbachol was recycled back to the cell membrane. PKC-epsilon-dependent alteration of NKCC1 surface expression represents a novel mechanism for regulating Cl(-) secretion.
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PMID:Dynamic regulation of Na(+)-K(+)-2Cl(-) cotransporter surface expression by PKC-{epsilon} in Cl(-)--secretory epithelia. 1600 Jun 38

We have explored the possible mechanisms by which mineralocorticoid (MR) and glucocorticoid (GR) receptors regulate the response to freshwater transfer in the gills of the euryhaline killifish Fundulus heteroclitus. Killifish were implanted with RU486 (GR antagonist) or spironolactone (MR antagonist) at doses of 0.1-1.0 mg g(-1), and subsequently transferred from 10 per thousand brackish water to freshwater. Compared to brackish water sham fish, mRNA expression of CFTR and NKCC1 decreased in the gills of sham fish transferred to freshwater, whereas Na(+), K(+)-ATPase alpha(1a) mRNA expression and alpha protein abundance, as well as cell proliferation (detected using BrdU) increased. Spironolactone inhibited the normal increase in cell proliferation and Na(+), K(+)-ATPase expression after freshwater transfer. RU486 increased plasma cortisol levels and may have slightly inhibited Na(+), K(+)-ATPase activity, but did not change alpha(1a ) expression. RU486 had no effect on cell proliferation in the non-lamellar region of the gills, but increased proliferation in the lamellar region. Neither antagonist inhibited the suppression of CFTR or NKCC1 expression after freshwater transfer. Glucocorticoid receptor expression was reduced in all sham and antagonist treatments compared to untreated controls, but no other consistent differences were observed. The effects of spironolactone suggest that MR is important for regulating ion transport in killifish gills after freshwater transfer.
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PMID:Effects of spironolactone and RU486 on gene expression and cell proliferation after freshwater transfer in the euryhaline killifish. 1608 94

NKCC1 null mice are hypotensive, in part, from the absence of NKCC1-mediated vasoconstriction. Whether these mice have renal defects in NaCl and water handling which contribute to the hypotension is unexplored. Therefore, we asked 1) whether NKCC1 (-/-) mice have a defect in the regulation of NaCl and water balance, which might contribute to the observed hypotension and 2) whether the hypotension observed in these mice is accompanied by endocrine abnormalities and/or downregulation of renal Na+ transporter expression. Thus we performed balance studies, semiquantitative immunoblotting, and immunohistochemistry of kidney tissue from NKCC1 (+/+) and NKCC1 (-/-) mice which consumed either a high (2.8% NaCl)- or a low-NaCl (0.01% NaCl) diet for 7 days. Blood pressure was lower in NKCC1 (-/-) than NKCC1 (+/+) mice following either high or low dietary NaCl intake. Relative to wild-type mice, NKCC1 null mice had a lower plasma ANP concentration, a higher plasma renin and a higher serum K+ concentration with inappropriately low urinary K+ excretion, although serum aldosterone was either the same or only slightly increased in the mutant mice. Expression of NHE3, the alpha-subunit of the Na-K-ATPase, NCC, and NKCC2 were higher in NKCC1 null than in wild-type mice, although differences were generally greater during NaCl restriction. NKCC1 null mice had a reduced capacity to excrete free water than wild-type mice, which resulted in hypochloremia following the NaCl-deficient diet. Hypochloremia did not occur from increased aquaporin-1 (AQP1) or 2 protein expression or from redistribution of AQP2 to the apical regions of principal cells. Instead, NKCC1 null mice had a blunted increase in urinary osmolality following vasopressin administration, which should increase free water excretion and attenuate the hypochloremia. In conclusion, aldosterone release is inappropriately low in NKCC1 null mice. Moreover, the action of aldosterone and vasopressin is altered within kidneys of NKCC1 null mice, which likely contributes to their hypotension. Increased Na+ transporter expression, increased plasma renin, and reduced plasma ANP, as observed in NKCC1 null mice, should increase vascular volume and blood pressure, thus minimizing hypotension.
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PMID:Hypotension in NKCC1 null mice: role of the kidneys. 1615 93

Previously (Wellner et al., Pflugers Arch 441:49-56, 2000) we suggested that the localization of the aquaporins (AQPs) AQP5 and AQP8 in the apical and basolateral membranes of rat submandibular gland (SMG) acinar cells, respectively, provides for transcellular water flow during saliva formation. While the localization of AQP5 in this gland has been verified in several laboratories, there have been differing reports regarding AQP8 localization. Other investigators subsequently reported that AQP8 is not expressed in the acinar or ductal cells of the major salivary glands of the rat, but in the myoepithelium of each gland. Thus, we have carried out additional studies: (1) to reassess the localization of AQP8 in the rat SMG and (2) to assess the localization of AQP8 in the rat parotid gland (PG). Initially, we compared the localizations of AQP8 with recognized basolateral markers in acinar cells [the Na+,K+-ATPase and the Na+-K+-2Cl- cotransporter (NKCC1)]. Our results indicated that Na+,K+-ATPase localized in both the basal and lateral membranes of rat SMG acinar cells, whereas AQP8 was detected only in the basal regions of the acini. In the rat PG, AQP8 was invested near intercalated ducts and adjacent acini, whereas NKCC1 localized in the basolateral membranes of acinar cells. As these results were suggestive of myoepithelial localization in both glands, we compared AQP8 localization with the localization of smooth muscle actin, a myoepithelial marker. We found that AQP8 and smooth muscle actin colocalized in both the rat SMG and PG, providing additional strong support for a myoepithelial localization of AQP8. Thus, in agreement with an earlier report by other investigators (Elkjaer et al., Am J Physiol Renal Physiol 281:F1047-F1057, 2001), we report that AQP8 is expressed in the myoepithelial cells, but not in the acinar cells, of both the rat SMG and PG.
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PMID:Further evidence for AQP8 expression in the myoepithelium of rat submandibular and parotid glands. 1631 20

The choroid plexus epithelium secretes electrolytes and fluid in the brain ventricular lumen at high rates. Several channels and ion carriers have been identified as likely mediators of this transport in rodent choroid plexus. This study aimed to map several of these proteins to the human choroid plexus. Immunoperoxidase-histochemistry was employed to determine the cellular and subcellular localization of the proteins. The water channel, aquaporin (AQP) 1, was predominantly situated in the apical plasma membrane domain, although distinct basolateral and endothelial immunoreactivity was also observed. The Na(+)-K(+)-ATPase alpha(1)-subunit was exclusively localized apically in the human choroid plexus epithelial cells. Immunoreactivity for the Na(+)-K(+)-2Cl(-) cotransporter, NKCC1, was likewise confined to the apical plasma membrane domain of the epithelium. The Cl(-)/HCO(3)(-) exchanger, AE2, was localized basolaterally, as was the Na(+)-dependent Cl(-)/HCO(3)(-) exchanger, NCBE, and the electroneutral Na(+)-HCO(3)(-) cotransporter, NBCn1. No immunoreactivity was found toward the Na(+)-dependent acid/base transporters NHE1 or NBCe2. Hence, the human choroid plexus epithelium displays an almost identical distribution pattern of water channels and Na(+) transporters as the rat and mouse choroid plexus. This general cross species pattern suggests central roles for these transporters in choroid plexus functions such as cerebrospinal fluid production.
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PMID:Distribution of sodium transporters and aquaporin-1 in the human choroid plexus. 1648 71

The post-macula densa segments of the renal tubule--that is, the distal convoluted tubule, connecting tubule, and collecting duct--play a central role in determining final urine sodium excretion. The major regulated sodium transporters and channels in these cell types include the thiazide-sensitive (Na-Cl) cotransporter (NCC), the epithelial sodium channel (ENaC), and Na-K-ATPase. Furthermore, although not involved in sodium reabsorption, the anion exchanger, pendrin, and the basolateral bumetanide-sensitive Na-K-2Cl cotransporter (NKCC1 or BSC2) have roles in blood-volume maintenance. Mutations in several of these major sodium transporters, channel subunits, and their regulatory proteins have been linked to human diseases such as Liddle's syndrome, Gitelman's syndrome, and Gordon's syndrome, emphasizing the need for appropriate regulation of sodium at these sites for maintenance of sodium balance and normotension.
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PMID:Sodium transporters in the distal nephron and disease implications. 1667 50

Inhibition of the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) with bumetanide reduced contractile responses to phenylephrine (PE) in male rat aortas (129+/-4% of 60 mM KCl-induced contraction control vs 108+/-7% bumetanide; PE 10(-5) M; P<0.01) but did not change equivalent responses in female rat aortas. Removal of the endothelium blunted the effect of NKCC1 inhibition on the response to PE (10(-5) M) in males, whereas in denuded aorta from female rats, bumetanide reduced this response (162+/-5% control vs 146+/-3% bumetanide; P<0.05). NKCC1 basal activity did not show gender differences in intact aortic rings, but in the presence of PE, bumetanide-sensitive (86)Rb(+)/K(+) uptake increased more in male than female aortas (179+/-8 in males vs 158+/-5 nmol (86)Rb(+)/K(+) min(-1) (g aorta)(-1) in females; P<0.05). PE did not stimulate NKCC1 activity in denuded aorta from male rats. However, in female rats, PE increased NKCC1 activity similarly in both denuded (169+/-11 nmol (86)Rb(+)/K(+) min(-1) (g aorta)(-1)) and intact aortas. Ovariectomy increased the bumetanide-sensitive (86)Rb(+)/K(+) uptake increase elicited by PE (223+/-17 nmol (86)Rb(+)/K(+) min(-1) (g aorta)(-1)) and hormone replacement with 17beta-estradiol prevented this effect (159+/-29 nmol (86)Rb(+)/K(+) min(-1) (g aorta)(-1)). Na(+),K(+)-ATPase basal activity, measured as ouabain-sensitive (86)Rb(+)/K(+) uptake, was similar in male and female rats, but the effect of PE was significantly less in intact male aortas (232+/-16 in males vs 296+/-25 nmol (86)Rb(+)/K(+) min(-1) (g aorta)(-1) in females; P<0.05). Our results suggest that PE induced activation of NKCC1 and Na(+),K(+)-ATPase in the rat aorta in a gender-dependent way.
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PMID:Na+ -K+ -2Cl- cotransporter is implicated in gender differences in the response of the rat aorta to phenylephrine. 1679 47


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