V. Gustavo Blanco, M.D., Ph.D.

The Na,K-ATPase is an enzyme of the plasma membrane of most animal cells, which hydrolyses ATP to transports cytoplasmic Na+ in exchange for extracellular K+. The Na,K-ATPase is critical in maintaining the cell volume and pH, the membrane excitability of muscle and nervous tissue, and the reabsorption of Na+ and water in the kidney. The transporter comprises a group of isozymes, each characterized by unique enzymatic properties and a cell-dependent and developmentally regulated pattern of expression. Na,K-ATPase isozyme diversity results from the association of different molecular forms of the α (α1, α2, α3, α4) and the β (β1, β2, β3) subunits that constitute the enzyme. In our laboratory we are interested in understanding the biological role of the various isozymes of the Na,K-ATPase in cell physiology. In particular, the function of α4, which is expressed in male germ cells. Our results show that α4 has functional properties different from those of the other Na,K-ATPase α isoforms, it is up-regulated during
gameto-genesis and is important for sperm motility.

Another area of research is focused to understanding the role of the Na,K-ATPase in autosomal dominant polycystic kidney disease (ADPKD), a genetic disorder characterized by the growth of fluid-filled vesicles in the kidney that distorts the structure and severely compromises the function of the organ. We have found that animal models of APKD, and kidney cells from patients with ADPKD, exhibit a Na,K-ATPase activity that is abnormally sensitive to ouabain, a hormone released by the adrenal glands of mammals. Circulating levels of ouabain causes inhibition of Na,K-ATPase activity in ADPKD cells, and also initiates a cascade of phosphorylating events that results in expression of genes responsible for cell growth and proliferation. Abnormal cell proliferation and changes in the transport properties of the tubular renal epithelium are major factors for the formation and maintenance of renal cysts. Therefore, the altered ouabain sensitive phenotype of ADPKD is an important novel mechanism for cystogenesis in the disease.