Stine Falsig Pedersen
Cell Biology and Physiology, University of Copenhagen |
Our overall objective is to increase the understanding of the regulation, physiology, and structure-function relationship of the ubiquitous plasma membrane Na+/H+ exchanger isoform 1 (NHE1), as well as of other pH regulatory ion transporters, in particular the Na+,HCO3- cotransporter NBCn1.
NHE1 is a member of the SLC9A family of Na+/H+ exchanger proteins. NHE1 is a highly conserved protein with central roles in the control of cell volume, intracellular pH, and cytoskeletal organization. Consequently, many pivotal cellular functions, including migration, proliferation, and cell death are dependent on NHE1.
Excessive NHE1 activity has been shown to play a major role in, on the one hand, cell damage and death after ischemia-reperfusion injuries (e.g. after a stroke or heart attack) and on the other hand, in several aspects of cancer development, including the accelerated growth and migratory/invasive properties of cancer cells.
Both the regulation and function of NHE1 are highly complex. NHE1 is activated by intracellular acidification, by a wide array of hormones and growth factors, and by osmotic cell shrinkage and other physical stimuli. In addition to being an ion transporter, NHE1 also plays physiological roles which are at least in part independent of the ions transported, but rather reflecting its functions as a scaffold for F-actin binding and cellular signaling.
The 3D structure of NHE1 is unknown, as are the locus and mechanism of ion translocation and interaction with commercially available inhibitors developed for clinical use. Given the widespread clinical importance of excessive NHE1 activity, and the paucity of data regarding the mechanisms by which carriers such as NHE1 mediate ion exchange, these issues are of substantial interest both in terms of basic research and in a clinical context. The tail region of NHE1 is known to be important for NHE1 regulation and function, however, the structure of this region is also essentially unelucidated.