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You searched for +publisher:"Rutgers University" +contributor:("Runnels, Loren W"). Showing records 1 – 2 of 2 total matches.

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Rutgers University

1. Cai, Na, 1988-. The functional interplay between TPRM7 channel-kinase autophosphorylation and its cellular regulation.

Degree: PhD, Pharmacology, Cellular and Molecular, 2018, Rutgers University

As a member of the transient receptor potential ion channel subfamily, TRPM7 is a remarkable ion channel in possession of its own functional kinase domain. TRPM7 is ubiquitously expressed and permeable to divalent cations, allowing Mg2+, Ca2+, and trace metals ions such as Zn2+ to constitute the channel’s characteristic small inward current. The channel’s functional kinase domain is located at the protein’s cytosolic COOH terminus, placing TRPM7 also into a family of serine/threonine-phosphorylating alpha-kinases. It is not intuitively clear why a channel is covalently linked to a kinase, especially as it has been found that the kinase activity of TRPM7 is not required for channel gating. Previous studies have shown that TRPM7 is autophosphorylated, and yet the functional outcome of this autophosphorylation remain unknown. Motivated to understand the impact of phosphorylation on the function and regulation of this channel-kinase, I performed a comprehensive phosphoproteomic analysis of TRPM7 by mass spectrometry to identify the major in vivo phosphorylation sites on TRPM7. The results of the mass spectrometry study uncovered potential mechanisms by which the catalytic activity of TRPM7 kinase is regulated through autophosphorylation. My experiments also revealed a significant role of TRPM7’s kinase activity in regulating the posttranslational processing of TRPM7. Utilizing the TRPM7-K1646R kinase-inactive mutant, I discovered that TRPM7 kinase inactivation leads to faster protein degradation and intracellular retention of the channel in polarized epithelial cells compared to the wildtype protein. Mutational analysis of TRPM7 autophosphorylation sites further revealed a role for S1360 as a key residue mediating both protein stability and intracellular trafficking of TRPM7. In addition, I discovered that the intrinsic kinase activity of TRPM7 mediates the interaction of the channel with the signaling protein 14-3-3θ, whose binding sites on TRPM7 also contribute to the regulation of TRPM7 trafficking. Overall, these findings expand our knowledge of the in vivo phosphorylation profile of TRPM7 and, more importantly, increase our understanding of the significance of TRPM7’s kinase for functional regulation of the channel.

Advisors/Committee Members: Runnels, Loren W (chair), Walworth, Nancy C (internal member), Madura, Kiran (internal member), Jin, Shengkan (Victor) (internal member), Stock, Ann M (outside member), School of Graduate Studies.

Subjects/Keywords: TRP channels

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Cai, Na, 1. (2018). The functional interplay between TPRM7 channel-kinase autophosphorylation and its cellular regulation. (Doctoral Dissertation). Rutgers University. Retrieved from https://rucore.libraries.rutgers.edu/rutgers-lib/57513/

Chicago Manual of Style (16th Edition):

Cai, Na, 1988-. “The functional interplay between TPRM7 channel-kinase autophosphorylation and its cellular regulation.” 2018. Doctoral Dissertation, Rutgers University. Accessed May 09, 2021. https://rucore.libraries.rutgers.edu/rutgers-lib/57513/.

MLA Handbook (7th Edition):

Cai, Na, 1988-. “The functional interplay between TPRM7 channel-kinase autophosphorylation and its cellular regulation.” 2018. Web. 09 May 2021.

Vancouver:

Cai, Na 1. The functional interplay between TPRM7 channel-kinase autophosphorylation and its cellular regulation. [Internet] [Doctoral dissertation]. Rutgers University; 2018. [cited 2021 May 09]. Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/57513/.

Council of Science Editors:

Cai, Na 1. The functional interplay between TPRM7 channel-kinase autophosphorylation and its cellular regulation. [Doctoral Dissertation]. Rutgers University; 2018. Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/57513/


Rutgers University

2. Lou, Liping, 1982-. Investigation of the function and regulation of the TRPM7 ion channel in the renal proximal tubule.

Degree: PhD, TRPM7, 2019, Rutgers University

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… Advisors/Committee Members: Runnels, Loren W (chair), Ryazanov, Alexey G (internal member), Sesti, Federico (internal member), Fan, Huizhou (outside member), School of Graduate Studies.

Subjects/Keywords: Pharmacology, Cellular and Molecular; TRP channels

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Lou, Liping, 1. (2019). Investigation of the function and regulation of the TRPM7 ion channel in the renal proximal tubule. (Doctoral Dissertation). Rutgers University. Retrieved from https://rucore.libraries.rutgers.edu/rutgers-lib/60852/

Chicago Manual of Style (16th Edition):

Lou, Liping, 1982-. “Investigation of the function and regulation of the TRPM7 ion channel in the renal proximal tubule.” 2019. Doctoral Dissertation, Rutgers University. Accessed May 09, 2021. https://rucore.libraries.rutgers.edu/rutgers-lib/60852/.

MLA Handbook (7th Edition):

Lou, Liping, 1982-. “Investigation of the function and regulation of the TRPM7 ion channel in the renal proximal tubule.” 2019. Web. 09 May 2021.

Vancouver:

Lou, Liping 1. Investigation of the function and regulation of the TRPM7 ion channel in the renal proximal tubule. [Internet] [Doctoral dissertation]. Rutgers University; 2019. [cited 2021 May 09]. Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/60852/.

Council of Science Editors:

Lou, Liping 1. Investigation of the function and regulation of the TRPM7 ion channel in the renal proximal tubule. [Doctoral Dissertation]. Rutgers University; 2019. Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/60852/

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