Research
Overview
Our laboratory studies the role of ion-transport proteins of the plasma membrane in cell function, with especial emphasis on the Na,K-ATPase.
Na,K-ATPase is present on the surface of most cells, where it moves Na+ from the cell in exchange for extracellular K+. Na,K-ATPase maintains cell volume and pH, excitability of muscle and nervous tissue, and is key for the reabsorption of salt and water in the kidney. Structurally, Na,K-ATPase is constituted by two major subunits; an alpha subunit, responsible for the transport functions of the Na,K-ATPase; and the beta polypeptide, which is important for targeting the transporter to the plasma membrane. Na,K-ATPase is expressed in different molecular variants or isozymes, each resulting from the association of distinct forms of the alpha (alpha 1, alpha 2, alpha 3 and alpha 4) and beta (beta 1, beta 2 and beta 3) subunits. A third protein, the gamma subunit is a Na,K-ATPase regulatory subunit only expressed in some tissues.
We are studying the structure function of Na,K-ATPase and the role of its various isozymes in cell physiology, applying a variety of molecular, cell biology and genetic tools. We and others have shown that different isoforms of the Na,K-ATPase have unique properties and are expressed in a tissue specific manner. Currently, we have focused our interest on the function of Na,K-ATPase alpha4, a testis specific isoform of Na,K-ATPase. We have found that Na,K-ATPase alpha4 is only expressed in male germ cells of the testis after meiosis and that it is abundant in the sperm flagellum. Na,K-ATPase alpha4 is critical for sperm motility and sperm from mice deficient in in this protein are completely infertile. Experiments are under way with the goal of using Na,K-ATPase as a marker for male fertility and as a target for male contraception.
Another project in our laboratory is directed to understand the role of the Na,K-ATPase in autosomal dominant polycystic kidney disease (ADPKD). ADPKD is a pathology characterized by the progressive enlargement of fluid filled cysts in the kidneys that compromise the function of the organ. We are studying the function of the Na,K-ATPase in kidneys from animal models of ADPKD and in renal epithelial cells from patients with ADPKD. We have found that in ADPKD, Na,K-ATPase has a higher sensitivity to the hormone ouabain and that physiological concentrations of ouabain stimulate ADPKD cystogenesis. We have characterized the pathways leading to the effects of ouabain in ADPKD cells and we are further investigating the mechanisms by which ouabain affects ADPKD cyst formation and development with the idea of targeting this mechanism to lessen ADPKD progression.
