The sodium/potassium-dependent adenosine triphosphatase (Na, K-ATPase) is the membrane protein that maintains the cell's Na/K electrochemical gradient via the active transport of Na and K across the plasma membrane. Directly and/or indirectly thru coupling with other cation transport mechanisms, it is involved in the regulation of cells volume and osmotic equilibrium, uptake of nutrients by the intestines, propagation of the action potential of nerve and muscle, modulation of synaptic action, uptake of solutes by the kidney, cell differentiation and proliferation. It has also been implicated in hypertension, brain edema and ischemia, manic depression, hepatic failure, ulcerative colitis, diabetic peripheral neuropathy, cystic fibrosis, and autohemolytic red cell membrane diseases. Its study is, therefore, important in basic and medical sciences. Molecular biology provides an incisive tool to the study of the Na-pump and coupled with cell biology and protein biochemistry, addresses more precisely the analysis of structure-function relationships and gene regulation of its subunit isoforms: alpha, the catalytic subunit, and beta, the glycosylated subunit. Using these tools this research proposes to study A) the molecular genetics of the Na-pump by aiming to 1) complete the structural analysis of the alpha subunit by the isolation of full length cDNA clones of the different isoforms and determining their tissue specific and developmental expression, and primary structure; 2) establish a tissue culture system to study the synthesis of the Na-pump and the structure-function relationships of its subunits; 3) assess the involvement of alpha subunits' long 5'UT region in the regulation of their respective expression; and 4) define the functional differences of the presently isolated alpha 1 and alpha 2 isoforms. It also proposes to study the Na-pump's possible involvement in hypertension by aiming to assess the modulation of expression of the Na-pump's alpha and beta isoforms in hypertension by in-situ hybridization using the spontaneously hypertensive and Dahlsalt susceptible rat genetic hypertension models. This research study will provide insight into the mechanisms of the Na-pump's general and highly specialized functions, as well as, insight into an intriguing aspect of hypertension, the role of Na transport. It will also pave the way for future research on precise mechanisms of Na,K-ATPase structure-function relationships and gene regulation in hypertension.
| Herrera, V L; Cova, T; Sassoon, D et al. (1994) Developmental cell-specific regulation of Na(+)-K(+)-ATPase alpha 1-, alpha 2-, and alpha 3-isoform gene expression. Am J Physiol 266:C1301-12 |
| Herrera, V L; Ruiz-Opazo, N (1990) Alteration of alpha 1 Na+,K(+)-ATPase 86Rb+ influx by a single amino acid substitution. Science 249:1023-6 |
| Herrera, V L; Chobanian, A V; Ruiz-Opazo, N (1988) Isoform-specific modulation of Na+, K+-ATPase alpha-subunit gene expression in hypertension. Science 241:221-3 |
