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Investigation of the function and regulation of the TRPM7 ion channel in the renal proximal tubule

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Title
Investigation of the function and regulation of the TRPM7 ion channel in the renal proximal tubule
Name (type = personal)
NamePart (type = family)
Lou
NamePart (type = given)
Liping
NamePart (type = date)
1982-
DisplayForm
Liping Lou
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Runnels
NamePart (type = given)
Loren W
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Loren W Runnels
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Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = personal)
NamePart (type = family)
Ryazanov
NamePart (type = given)
Alexey G
DisplayForm
Alexey G Ryazanov
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Advisory Committee
Role
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internal member
Name (type = personal)
NamePart (type = family)
Sesti
NamePart (type = given)
Federico
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Federico Sesti
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Fan
NamePart (type = given)
Huizhou
DisplayForm
Huizhou Fan
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
outside member
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
School of Graduate Studies
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (encoding = w3cdtf); (keyDate = yes); (qualifier = exact)
2019
DateOther (encoding = w3cdtf); (qualifier = exact); (type = degree)
2019-05
CopyrightDate (encoding = w3cdtf); (qualifier = exact)
2019
Language
LanguageTerm (authority = ISO 639-3:2007); (type = text)
English
Abstract (type = abstract)
The TRPM7 (Transient Receptor Potential Melastatin 7) ion channel is a unique member of the TRP channel family, possessing its own functional kinase domain at its COOH-terminus. As a Mg2+-permeable ion channel, TRPM7 has frequently been linked to the regulation of magnesium reabsorption at both the cellular and whole-body level. Mg2+ plays a pivotal role in human health and disease, and therefore, its level in the body has to be tightly regulated via ion channels and transporters in the functional unit of the kidney, the nephron. TRPM6, the close homolog of TRPM7, has been identified to be the major player regulating Mg2+ reabsorption in the distal convoluted tubule of the nephron. A major gap in our knowledge of TRPM7 is whether the channel is involved in regulating magnesium homeostasis in the proximal tubule of the nephron, where TRPM7 is highly expressed.
To gain insight into the function of TRPM7 in the proximal tubule, we generated two conditional strains of proximal tubule-specific trpm7 KO mice, using PEPCK-Cre and gGT-Cre mice. The Mg2+ status of the proximal tubule trpm7 knockout mice was assessed but we did not obtain any evidence that the Mg2+ homeostasis was disrupted in the animals, indicating TRPM7 does not play a major role in proximal tubule to regulate whole-body magnesium homeostasis. However, large cavities and reduced cortical layers in the kidney anatomy of some female gGT-Cre KO trpm7 mice were observed. TRPM7 has previously been implicated in the regulation of cell-cell adhesion, having recently been found to contribute to the intercellular junction formation in the bladder urothelium. We performed transmission electron microscopy (TEM) analysis of the tissue slides obtained from the cortex of the kidneys from gGT-Cre KO trpm7 mice and found that tubule epithelial cells from the trpm7 KO mice had more impaired intercellular junctions than that from the control mice.
We next investigated the relationship between TRPM7 and cell-cell adhesion process, employing the proximal tubule epithelial cell line, opossum kidney (OK) cells, as a cellular model. Mass spectrometric analysis uncovered that TRPM7 interacted with a cell adhesion protein called plakoglobin. Using immunocytochemical assays, we discovered that TRPM7 co-localized with plakoglobin and another adherens junction protein called E-cadherin. Application of the TRPM7’s channel blocker NS8593 to OK cells reduced E-cadherin expression and localization to adherens junctions. Taken together, these data suggest that TRPM7 is involved in controlling cell-cell adhesion in proximal tubule epithelial cells.
In this study, we also explored the mechanism(s) by which TRPM7’s cellular localization is regulated. Using biochemical and immunocytochemical approaches, we identified a regulatory site at the COOH-terminus of TRPM7, the channel’s PDZ-binding motif, through which the localization of TRPM7 in OK cells could be regulated. Deletion of the channel’s PDZ-binding motif shortened the retention time of the mutant TRPM7 (TRPM7ΔPDZ) at adherens junctions of OK cells. We also discovered that TRPM7’s localization to the adherens junctions in OK cells was potentiated by the activation of PKC, indicating that TRPM7 localization is potentially regulated by the PKC pathway.
While our understanding of the relationship between TRPM7 and cell-cell adhesion is still in its infancy, the discoveries made in this study will guide future investigations into the physiological roles of the channel in the regulation of cell-cell adhesion.
Subject (authority = local)
Topic
TRPM7
Subject (authority = RUETD)
Topic
Pharmacology, Cellular and Molecular
Subject (authority = LCSH)
Topic
TRP channels
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
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ETD_9797
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application/pdf
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text/xml
Extent
1 online resource (x, 110 pages) : illustrations
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
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School of Graduate Studies Electronic Theses and Dissertations
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rucore10001600001
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NjNbRU
Identifier (type = doi)
doi:10.7282/t3-qwdk-0c36
Genre (authority = ExL-Esploro)
ETD doctoral
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The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Lou
GivenName
Liping
Role
Copyright Holder
RightsEvent
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Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2019-04-12 16:04:33
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Name
Liping Lou
Role
Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
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I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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