Na+,K+-activated adenosine triphosphatase (Na,K-ATPase, Na/K- pump) is a ubiquitous plasma membrane enzyme of central importance in animal cell physiology. Through its continuous function, Na+ and K+ ions are actively transported across the plasma membrane, and the transmembrane gradients for these ions are maintained. The Na+ electrochemical gradient is in turn utilized by a variety of carrier-mediated symport and antiport processes in the transport of ions, nutrients and other products across the plasma membrane. The determinants of the number and activity of Na,K-ATPase molecules, however, and the quantitative relationship between the tissue abundance of Na,K- ATPase subunit mRNA's (mRNA alpha and mRNA beta) and the activity of Na,K-ATPase under physiological conditions have not yet been elucidated. Equally unknown are the rates of synthesis and degradation of Na,K-ATPase mRNA's under steady-state conditions and the potential effects of modulators of the enzyme activity on the turnover of these mRNA's. In the past two years the applicant has characterized two rat liver cell lines that respond to thyroid hormone (T3) and other physiological pertubations in vitro, and has additionally employed newly available specific cDNA probes to determine the cellular abundance of mRNA alpha and mRNA beta encoding the Na, K- ATPase molecule. In the proposed project, the applicant will employ these specific cDNA probes in order to examine rates of transcription of nascent mRNA alpha and mRNA beta as well as rates of synthesis and degradation of the fully processed mRNA's in intact cells under basal physiological conditions. The availability of these T3-responsive cell lines will additionally make possible the elucidation of mechanisms underlying the well known induction of Na,K-ATPase enzymatic pump sites by T3 as well as the accompanying T3-induced increments in the steady- state levels of the corresponding mRNA's which we have recently described. The specific effects of T3 in stimulating the transcription rates of Na,K-ATPase mRNA's and in retarding their degradation (""""""""mRNA stabilization"""""""") will be evaluated. The resulting detailed information should provide not only a molecular basis for the physiological regulation of Na,K-ATPase under basal state and in response to thyroid hormone, but in addition a mechanistic foundation for future investigation of other physiologically altered metabolic states.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Physiology Study Section (PHY)
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Columbia University (N.Y.)
Schools of Medicine
New York
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Morris, J F; Ismail-Beigi, F; Butler Jr, V P et al. (1997) Ouabain-sensitive Na+,K(+)-ATPase activity in toad brain. Comp Biochem Physiol A Physiol 118:599-606
Kirtane, A; Ismail-Beigi, N; Ismail-Beigi, F (1994) Role of enhanced Na+ entry in the control of Na,K-ATPase gene expression by serum. J Membr Biol 137:9-15
Higham, S C; Melikian, J; Karin, N J et al. (1993) Na,K-ATPase expression in C2C12 cells during myogenesis: minimal contribution of alpha 2 isoform to Na,K transport. J Membr Biol 131:129-36
Shetty, M; Loeb, J N; Ismail-Beigi, F (1992) Enhancement of glucose transport in response to inhibition of oxidative metabolism: pre- and posttranslational mechanisms. Am J Physiol 262:C527-32
Hakimian, J; Ismail-Beigi, F (1991) Enhancement of glucose transport in clone 9 cells by exposure to alkaline pH: studies on potential mechanisms. J Membr Biol 120:29-39
Kuruvilla, A K; Perez, C; Ismail-Beigi, F et al. (1991) Regulation of glucose transport in Clone 9 cells by thyroid hormone. Biochim Biophys Acta 1094:300-8
Bhutada, A; Ismail-Beigi, F (1991) Serum and growth factor induction of Na(+)-K(+)-ATPase subunit mRNAs in Clone 9 cells: role of protein kinase C. Am J Physiol 261:C699-707
Bhutada, A; Wassynger, W W; Ismail-Beigi, F (1991) Dexamethasone markedly induces Na,K-ATPase mRNA beta 1 in a rat liver cell line. J Biol Chem 266:10859-66
Perez, C; Bhutada, A; Ismail-Beigi, F (1991) Induction of Na(+)-K(+)-ATPase subunit mRNAs by cycloheximide in a rat liver cell line. Am J Physiol 260:C417-23
Gick, G G; Ismail-Beigi, F (1990) Thyroid hormone induction of Na(+)-K(+)-ATPase and its mRNAs in a rat liver cell line. Am J Physiol 258:C544-51

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