Regulation of Sodium Pump Expression in Cardiac Cells
Na,K-ATPase (Na,K-pump) is a ubiquitous plasma membrane-bound enzyme that plays an essential role in animal physiology. Na,K-ATPase extrudes three Na ions from within the cell and accumulates two K ions at the expense of ATP, thereby directly maintaining transmembrane gradients of Na and K of all animal cells. The Na,K-pump indirectly regulates cell volume and several cotransport systems (e.g., Ca, hydrogen ion, amino acids and glucose) are dependent on the potential energy of the transmembrane Na electrochemical gradient. Furthermore, Na,K-ATPase-dependent ion gradients generate the action potential of excitable cells such as cardiac myocytes and are necessary for proper regulation of contractility. Not only does Na,K-ATPase activity directly contribute to the steady-state action potential, physiological or pharmacological depression of Na,K-ATPase raises intracellular Na, thereby inhibiting Na/Ca exchanger activity with a resultant elevation of the intracellular concentration of Ca. The increase in intracellular Ca in response to direct inhibition of Na,K-ATPase represents the underlying molecular event in the inotropic action of cardiac glycosides used in the treatment of congestive heart failure.
The Na,K-pump is a heteromeric enzyme consisting of two noncovalently linked, dissimilar subunits, a and b, present in equimolar amounts. The larger a subunit (112 kDa) is responsible for catalysis and is the pharmacological receptor for cardiac glycosides such as digoxin. The glycosylated b subunit (53 kDa) is crucial for Na,K-pump function as it facilitates a/b heterodimer formation and subsequent transport of the holoenzyme to the plasma membrane. While multiple isoforms of Na,K-ATPase a (a1, a2, a3, a4) and b (b1, b2, b3) subunits are expressed in a tissue-specific fashion, a1 and b1 subunits are constitutively expressed in the majority of tissues. Moreover, in primary cultures of neonatal rat cardiac myocytes a1 and b1 represent the predominate isoforms.
Na,K-ATPase activity is subjected to both acute and long-term regulation by a myriad of positively and negatively acting physiological factors. A fundamental response of normal mammalian cells to prolonged inhibition of Na,K-pump function is a subsequent enhanced biosynthesis of Na,K-pump subunits yielding an increase in Na,K-ATPase activity. The importance of this adaptive, homeostatic mechanism is underscored by the association of reduced Na,K-pump expression and the development and/or pathogenesis of several disease states including hypertension, congestive heart failure, chronic renal failure and diabetes. We and others have modeled this homeostatic response by incubating cells in a low K-containing medium, thereby inhibiting Na,K-ATPase activity by substrate limitation. Our laboratory has demonstrated low K-mediated up-regulation of Na,K-ATPase a1 and b1 subunit gene expression in neonatal rat cardiac myocytes. Moreover, we are the first laboratory to have delineated the DNA sequence element and transcription factors that mediate low K-stimulation of Na,K-ATPase b1 subunit gene transcription. The ongoing research in our laboratory is focused on investigation of the molecular mechanisms underlying regulation of Na,K-pump expression by low K.
1. Isenovic, E.R.., Jacobs, D.B., Kedees, M.H., Sha, Q., Milivojevic, N., Kawakami, K., Gick, G. and Sowers, J.R. (2004) "Ang II regulation of the Na pump involves the PI3Kand p42/44 MAPK signaling pathways in VSMC." Endocrinology. 145:1151-1160. Read More Here
2. Wendt, C.H., Gick, G., Sharma, R., Zhuang, Y. Deng, W., Ingbar, D.H. (2000) "Upregulation of Na,K-ATPase β1 transcription is mediated by SP1/SP3." J. Biol. Chem. 275:41396-4140. Read More Here
3. Zhuang, Y., Wendt, C. and Gick, G. (2000) "Regulation of Na,K-ATPase β1 subunit gene transcription by low external potassium in cardiac myocytes.” Role of Sp1 and Sp3. J. Biol. Chem. 275:24173-24184. Read More Here
4. Kometiani, P., Tian, J., Li, J., Nabih, Z., Gick, G. and Zie, Z. (2000) "Regulation of Na/K-ATPase α1-subunit gene expression by ouabain and other hypertrophic stimuli in neonatal rat cardiac myocytes". Mol. Cell. Biochem. 215:65-72. Read More Here
5. Wendt, C.H., Sharma, R., Towle, H., Gick, G., Ingbar, D.H. (1999) "Hyperoxia upregulates Na,K-ATPase beta-1 gene transcription". Chest 115:87S-88S. Read More Here
6. Wendt, C.H., Towle, H., Sharma, R., Duvick, S.E., Kawakami, K., Gick, G. and Ingbar, D.H. (1998) "Regulation of Na,K-ATPase gene expression by hyperoxia in MDCK cells". Amer. J. Physiol. 274:C356-C364. Read More Here
7. Gidh-Jain, M., Huang, B., Jain, P., Gick, G. and El-Sherif, N. (1998) "Alterations in cardiac gene expression during ventricular remodeling following experimental myocardial infarction". J. Mol. Cell. Cardiol. 30:627-637. Read More Here
8. Chin, S., Apriletti, J. and Gick, G. (1998) "Characterization of a negative thyroid hormone response element in the rat Na,K-ATPase α3 gene promoter". Endocrinology.:139:3423-3431. Read More Here
9. Chin, S., He, H. and Gick, G. (1998) "Selective induction of Na,K-ATPase α3 subunit mRNA abundance in cardiac myocytes by retinoic acid:. J. Mol. Cell Cardiol. 30:2403-2410. Read More Here
10. He, H., Chin, S., Zhuang, K., Hartong, R., Apriletti, J. and Gick, G. (1996) "Negative regulation of the rat Na,K-ATPase α3 subunit gene promoter by thyroid hormone." Amer. J. Physiol. 271:C1750-C1756. Read More Here