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排序方式: 共有255条查询结果,搜索用时 31 毫秒
51.
52.
53.
Kenneth R. Hallows Huamin Wang Robert S. Edinger Michael B. Butterworth Nicholas M. Oyster Hui Li Jochen Buck Lonny R. Levin John P. Johnson N��ria M. Pastor-Soler 《The Journal of biological chemistry》2009,284(9):5774-5783
Alkalosis impairs the natriuretic response to diuretics, but the underlying
mechanisms are unclear. The soluble adenylyl cyclase (sAC) is a chemosensor
that mediates bicarbonate-dependent elevation of cAMP in intracellular
microdomains. We hypothesized that sAC may be an important regulator of
Na+ transport in the kidney. Confocal images of rat kidney revealed
specific immunolocalization of sAC in collecting duct cells, and immunoblots
confirmed sAC expression in mouse cortical collecting duct
(mpkCCDc14) cells. These cells exhibit aldosterone-stimulated
transepithelial Na+ currents that depend on both the apical
epithelial Na+ channel (ENaC) and basolateral
Na+,K+-ATPase. RNA interference-mediated 60-70%
knockdown of sAC expression comparably inhibited basal transepithelial short
circuit currents (Isc) in mpkCCDc14 cells.
Moreover, the sAC inhibitors KH7 and 2-hydroxyestradiol reduced
Isc in these cells by 50-60% within 30 min.
8-Bromoadenosine-3′,5′-cyclic-monophosphate substantially rescued
the KH7 inhibition of transepithelial Na+ current. Aldosterone
doubled ENaC-dependent Isc over 4 h, an effect that was
abolished in the presence of KH7. The sAC contribution to
Isc was unaffected with apical membrane nystatin-mediated
permeabilization, whereas the sAC-dependent Na+ current was fully
inhibited by basolateral ouabain treatment, suggesting that the
Na+,K+-ATPase, rather than ENaC, is the relevant
transporter target of sAC. Indeed, neither overexpression of sAC nor treatment
with KH7 modulated ENaC currents in Xenopus oocytes. ATPase and
biotinylation assays in mpkCCDc14 cells demonstrated that sAC
inhibition decreases catalytic activity rather than surface expression of the
Na+,K+-ATPase. In summary, these results suggest that
sAC regulates both basal and agonist-stimulated Na+ reabsorption in
the kidney collecting duct, acting to enhance
Na+,K+-ATPase activity.Maintenance of intracellular pH depends in part on the extracellular to
intracellular Na+ gradient, and elevation of intracellular
[Na+] can lead to acidification of the cytoplasm. It has been shown
that acidification of the cytoplasm of cells from frog skin and toad bladder
by increased partial pressure of CO2 reduces Na+
transport and permeability (1,
2). Conversely, the rise in
plasma bicarbonate caused by metabolic alkalosis with chronic diuretic use has
been shown to increase net renal Na+ reabsorption independently of
volume status, electrolyte depletion, and/or increased aldosterone secretion
(3,
4). However, the underlying
mechanisms involved in these phenomena remain unclear.The soluble adenylyl cyclase
(sAC)2 is a
chemosensor that mediates the elevation of cAMP in intracellular microdomains
(5-7).
Unlike transmembrane adenylyl cyclases (tmACs), sAC is insensitive to
regulation by forskolin or heterotrimeric G proteins
(8) and is directly activated
by elevations of intracellular calcium
(9,
10) and/or bicarbonate ions
(11). Thus, sAC mediates
localized intracellular increases in cAMP in response to variations in
bicarbonate levels or its closely related parameters, partial pressure of
CO2 and pH. Mammalian sAC is more similar to bicarbonate-regulated
cyanobacterial adenylyl cyclases than to other mammalian nucleotidyl cyclases,
which may indicate that there is a unifying mechanism for the regulation of
cAMP signaling by bicarbonate across biological systems. Although sAC appears
to be encoded by a single gene, there is significant isoform diversity for
this ubiquitously expressed enzyme
(11,
12) generated by alternative
splicing (reviewed in Ref.
13). sAC has been shown to
regulate the subcellular localization and/or activity of membrane transport
proteins such as the vacuolar H+-ATPase (V-ATPase) and cystic
fibrosis transmembrane conductance regulator in epithelial cells
(14,
15). Functional activity of
sAC has been reported in the kidney
(16), and sAC has been
localized to epithelial cells in the distal nephron
(14,
17).Given that natriuresis is decreased during metabolic alkalosis, when
bicarbonate is elevated, and Na+ reabsorption is impaired by high
partial pressure of CO2, we hypothesized that bicarbonate-regulated
sAC may play a key role in the regulation of transepithelial Na+
transport in the distal nephron. Reabsorption of Na+ in the kidney
and other epithelial tissues is mediated by the parallel operation of apical
ENaC and basolateral Na+,K+-ATPase, and both transport
proteins can be stimulated by cAMP via the cAMP-dependent protein kinase (PKA)
(18,
53). The aims of this study
were to investigate the role of sAC in the regulation of transepithelial
Na+ transport in the kidney through the use of specific sAC
inhibitors and electrophysiological measurements. We found that sAC inhibition
blocks transepithelial Na+ reabsorption in polarized
mpkCCDc14 cells under both basal and hormone-stimulated conditions.
Selective membrane permeabilization studies revealed that although ENaC
activity appears to be unaffected by sAC inhibition, flux through the
Na+,K+-ATPase is sensitive to sAC modulation. Inhibiting
sAC decreases ATPase activity without affecting plasma membrane expression of
the pump; thus, tonic sAC activity appears to be required for Na+
reabsorption in kidney collecting duct. 相似文献
54.
Butterworth MB Edinger RS Silvis MR Gallo LI Liang X Apodaca G Frizzell RA Fizzell RA Johnson JP 《American journal of physiology. Renal physiology》2012,302(5):F581-F590
Expression of the epithelial sodium channel (ENaC) at the apical membrane of cortical collecting duct (CCD) principal cells is modulated by regulated trafficking mediated by vesicle insertion and retrieval. Small GTPases are known to facilitate vesicle trafficking, recycling, and membrane fusion events; however, little is known about the specific Rab family members that modify ENaC surface density. Using a mouse CCD cell line that endogenously expresses ENaC (mpkCCD), the channel was localized to both Rab11a- and Rab11b-positive endosomes by immunoisolation and confocal fluorescent microscopy. Expression of a dominant negative (DN) form of Rab11a or Rab11b significantly reduced the basal and cAMP-stimulated ENaC-dependent sodium (Na(+)) transport. The greatest reduction in Na(+) transport was observed with the expression of DN-Rab11b. Furthermore, small interfering RNA-mediated knockdown of each Rab11 isoform demonstrated the requirement for Rab11b in ENaC surface expression. These data indicate that Rab11b, and to a lesser extent Rab11a, is involved in establishing the constitutive and cAMP-stimulated Na(+) transport in mpkCCD cells. 相似文献
55.
56.
57.
A family of genes located on four separate 32-kilobase circular plasmids in Borrelia burgdorferi B31. 总被引:9,自引:4,他引:5
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We have identified four loci in Borrelia burgdorferi B31 that contain open reading frames capable of encoding six proteins that are related to the antigenic proteins OspE and OspF. We have designated these proteins Erp, for OspEF-related protein, and named their respective genes erp. The erpA and erpB genes are linked, as are erpC and erpD, and the pairs probably constitute two operons. The erpG and erpH genes appear to be monocistronic. The ErpA and ErpC proteins are expressed by B. burgdorferi B31 in culture and are recognized by a polyclonal antiserum raised against the OspE protein of B. burgdorferi N40. The four erp loci are each located on different 32-kb circular plasmids that contain additional DNA sequences that are homologous to each other and to an 8.3-kb circular plasmid of B. burgdorferi sensu lato Ip2l. All four 32-kb plasmids can be maintained within a single bacterium, which may provide a model for the study of plasmid replication and segregation in B. burgdorferi. 相似文献
58.
Seiji Kudoh Qiu Wang Oscar F. Hidalgo Pat Rayman Raymond R. Tubbs Mark G. Edinger Ronald Bukowski James H. Finke 《Cancer immunology, immunotherapy : CII》1995,41(3):175-184
T cells infiltrating (T-TIL) B cell non-Hodgkin's lymphomas (NHL) are thought to represent a local host response to the tumor. However, tumor progression in the presence of this T cell infiltrate suggests that the T-TIL may be functionally impaired. To address this issue we determined whether response to stimulation of T-TIL from 25 patients with NHL through the T cell receptor (TCR/CD3) and the interleukin-2 (IL-2) receptor (IL-2R) was intact, since activation of these receptors is important for proliferation and cytokine production. Our results demonstrate defects in response to stimulation via TCR/CD3 and the IL-2R in T-TIL cells from patients with NHL that were not observed with T cells from the peripheral blood. T-TIL showed minimal proliferation to anti-CD3 and only modest proliferation to IL-2 alone or when combined with anti-CD3. Moreover, cytokine production in T-TIL was impaired since stimulation through the TCR/CD3 complex did not induce mRNA for interferon (IFN), IL-2, IL-4 or IL-10. The functional unresponsiveness of these cells may be linked to altered signalling through the TCR/CD3 since an abnormal tyrosine phosphorylation pattern was detected in T-TIL after stimulation with anti-CD3. 相似文献
59.
Characterization of cp18, a naturally truncated member of the cp32 family of Borrelia burgdorferi plasmids. 总被引:4,自引:0,他引:4
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B Stevenson S Casjens R van Vugt S F Porcella K Tilly J L Bono P Rosa 《Journal of bacteriology》1997,179(13):4285-4291
We have mapped the genes encoding the antigenic lipoproteins OspE and OspF to an approximately 18-kb circular plasmid in Borrelia burgdorferi N40. Sequencing and restriction mapping have revealed that this plasmid, cp18, is homologous to an 18-kb region of the cp32 circular plasmids found in the Lyme disease spirochetes. Our data show that cp18 may have arisen from an ancestral cp32 plasmid by deletion of a 14-kb region of DNA, indicating that a significant portion of the cp32 plasmid is not essential in cis for plasmid maintenance. These findings suggest that a relatively small recombinant plasmid capable of being stably maintained in B. burgdorferi could be constructed from a cp32 plasmid. 相似文献
60.
Homology throughout the multiple 32-kilobase circular plasmids present in Lyme disease spirochetes. 总被引:29,自引:9,他引:20
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We have characterized seven different 32-kb circular plasmids carried by Borrelia burgdorferi isolate B31. Restriction endonuclease recognition site mapping and partial sequencing of these plasmids indicated that all seven are probably closely related to each other throughout their lengths and have substantial relationships to cp8.3, an 8.3-kb circular plasmid of B. burgdorferi sensu lato isolate Ip21. With the addition of the seven 32-kb plasmids, this bacterial strain is known to carry at least 10 linear and 9 circular plasmids. Variant cultures of B. burgdorferi B31 lacking one or more of the 32-kb circular plasmids are viable and, at least in some cases, infectious. We have examined a number of different natural isolates of Lyme disease borreliae and found that all of the B. burgdorferi sensu stricto isolates and most of the B. burgdorferi sensu lato isolates tested appear to carry multiple 32-kb circular plasmids related to those of B. burgdorferi B31. The ubiquity of these plasmids suggests that they may be important in the natural life cycle of these organisms. They may be highly conjugative plasmids or prophage genomes, which could prove to be useful in genetically manipulating B. burgdorferi. 相似文献