Elucidation of the pathways leading to inactivation and degradation of the sodium / hydrogen exchanger isoform 1 (NHE1)

Introduction Sodium / hydrogen exchangers (NHEs) are ubiquitous ion transport proteins present in bacteria, plants, fungi and animals. 10 mammalian NHE isoforms have been cloned so far (named NHE1-9 and sperm NHE). In mammals (including humans), NHE1 is the most widely expressed isoform - it is present on all cells. It localizes to the outer surface membrane of the cell ("plasma membrane") and extrudes protons from the cell interior and imports sodium in the cell. This causes cell alkalinisation, increased intracellular sodium concentration and consequently cell swelling. Cell shrinkage, cytoplasmic acidification and growth factors are the strongest activators of NHE1. NHE1 is crucial for a wide variety of cellular processes such as cell pH regulation, volume defense and cell growth. At the whole organism level, NHE1 is important in cancer biology, central nervous system integrity and cardiovascular pathophysiology. NHE1-deficient cells are defective in adhesion, migration and proliferation. Tumor cells express high levels of NHE1, which enhances their potential for growth and metastasis. Currently, specific NHE1 inhibitors are being tested in humans in the setting of myocardial infarction, tumor growth, arterial hypertension and heart failure. Project Although this protein is very important in human biology, little is known about how its presence on the cell surface is regulated. The aim of this proposal is to determine the factors and processes underlying NHE1 inactivation on the plasma membrane, internalization from the plasma membrane and degradation in the cell under normal physiological and pathophysiological conditions. For our studies, we will use cultured mammalian cells (tissue culture) and a wide set of molecular biology techniques. To generate monocloncal antibodies as important study tools for our project, we will have to use 4-6 mice. The function of NHE1 will be measured by electrical methods (electrophysiology) in cultured mammalian cells. Outlook As there is no doubt about the pivotal importance of NHE1 in humans and mammals in general, discoveries in the field will have major impacts on the biology of cell pH and volume regulation, cell growth and cell motility. On a translational level, a better understanding of NHE1 regulation will change the way we look at cancer and cardiovascular disease. It will accelerate the development and testing of novel pharmacologic agents for cancer, hypertension, ischemic heart, cerebral and kidney disease. Diseases, notabene, which are responsible for the bulk of hospitalisations, disability and death in modern civilizations, thereby posing a major burden to our health care system.

Investigator
Dr. Daniel Fuster

Sponsor
Swiss National Foundation, Project no. 117732