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The N-terminus of a1 Subunit and Na/K-ATPase-Mediated Signal Transduction

Chen, Yi Liang
http://rave.ohiolink.edu/etdc/view?acc_num=mco1265032610

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2009, Doctor of Philosophy in Biomedical Sciences (Ph.D.), University of Toledo, College of Medicine.
Recent studies have ascribed many non-pumping functions to theNa/K-ATPase and it has been demonstrated to interact with a variety of proteins via its cytosolic N-terminus domain (NT), which plays an essential role for its non-pumping functions. One of the proteins that interact with NT is caveolin-1 that is implicated in cellular cholesterol trafficking and homeostasis. Since we previously showed that the Na/K-ATPase regulated membrane trafficking of caveolin-1, in this study we have further revealed that the Na/K-ATPase is able to regulate cellular cholesterol distribution via its interaction with cavelin-1. Graded knockdown of the Na/K-ATPase leads to redistribution of cholesterol from membranes to the cytosol and this effect is independent of its pumping function. Moreover, this regulation is confirmed in α1+/- mouse liver. Functionally, the knockdown-induced redistribution appears to affect the cholesterol sensing in the endoplasmic reticulum because it activates the sterol regulatory element binding protein pathway in vivo. Interestingly, our subsequent study has demonstrated that plasma membrane cholesterol also regulates the cell surface Na/K-ATPase α1 subunit by modulating membrane trafficking of α1. Depletion of plasma membrane cholesterol leads to endocytosis of α1 and accumulation of α1 in the late endosome/lysosomes. Mechanistically, the cholesterol-regulated α1 trafficking appears to be related to cholesterol-α1 interaction at the cholesterol recognition/interaction amino acid consensus site (CRAC) within NT. Disruption of the cholesterol-α1 interaction by mutating the key amino acid in CRAC blunts the regulation of the Na/K-ATPase trafficking by cholesterol. Thus, our studies have revealed a reciprocal regulation between the plasma membrane Na/K-ATPase and cholesterol and the Na/K-ATPase may represent a potential plasma membrane cholesterol sensor for the regulation of cellular cholesterol. Furthermore, since the Na/K-ATPase is a signaling molecule that controls kinase activities, the reciprocal regulation between the Na/K-ATPase and cholesterol may serve as an important link between kinase cascades and lipid homeostasis. To study the physiological role of the receptor function of the Na/K-ATPase, we first revealed that Cav-1 KO mice developed salt-sensitive hypertension, which implicated the signaling Na/K-ATPase in blood pressure regulation. Furthermore, we generated NT-YFP-expressing transgenic mice and showed that renal NT-YFP expression results in salt-sensitive hypertension. Mechanistically, development of salt-sensitive hypertension is related to renal membrane α1 and sodium hydrogen exchanger 3 trafficking and urine excretion of the endogenous Na/K-ATPase ligand, marinobufagenin, which may influence renal sodium reabsorption and excretion. Taken together, this study has demonstrated that the Na/K-ATPase α1 subunit plays important roles in cellular cholesterol homeostasis and is also regulated by plasma membrane cholesterol content. Moreover, in vivo expression of NT-YFP affects α1 trafficking and leads to salt-sensitive hypertension, which warrants further examination of the physiological role of the Na/K-ATPase α1 in the renal and cardiovascular systems.
Zi-Jian Xie, Ph.D. (Committee Chair)
Sonia Najjar, Ph.D. (Committee Member)
Joseph Shapiro, M.D. (Committee Member)
David Giovannucci, Ph.D. (Committee Member)
William Maltese, Ph.D. (Committee Member)
149 p.
Molecular Biology
cholesterol; Na/K-ATPase; metabolism; caveolin; hypertension

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Citations

  • Chen, Y. L. (2009). The N-terminus of a1 Subunit and Na/K-ATPase-Mediated Signal Transduction [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1265032610

    APA Style (7th edition)

  • Chen, Yi Liang. The N-terminus of a1 Subunit and Na/K-ATPase-Mediated Signal Transduction. 2009. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1265032610.

    MLA Style (8th edition)

  • Chen, Yi Liang. "The N-terminus of a1 Subunit and Na/K-ATPase-Mediated Signal Transduction." Doctoral dissertation, University of Toledo, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=mco1265032610

    Chicago Manual of Style (17th edition)

mco1265032610
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© 2009, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.