Primary fields of research

The NHE1 lab

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).

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.

Our research interests fall in two broad categories:

• Studies of the regulation and physiology of NHE1, in particular with respect to the roles of NHE1 in cell migration and in the cellular stress response
• Structure-function studies of the transmembrane and cytosolic regions of NHE1
  

For further information, please see our NHE1 lab homepage: http://www1.bio.ku.dk/english/research/cu/cf/nhe1/

Selected recent publications

Pedersen, S.F., and Cala, P.M. 2004. Comparative biology of the ubiquitous Na+/H+ exchanger, NHE1: lessons from erythrocytes. J. Exp. Zool., 301A:569-578

Pedersen, S.F., Owsianik, G., and Nilius, B. 2005. TRP channels: an overview. Cell Calcium 38: 233-252

Pedersen, S.F. 2006. The Na+/H+ exchanger NHE1 in stress-induced signal transduction: Implications for cell proliferation and cell death. Eur J Physiol. 452(3):249-59

Pedersen, S.F., O'Donnell, M.E., Anderson, S.E., Cala, P.M. 2006. Physiology and Pathophysiology of Na+/H+ exchange and Na+,K+,2Cl- cotransport. Am J Physiol 291(1):R1-25

Pedersen SF, Darborg BV, Rentsch ML, and Rasmussen M. 2007. Regulation of mitogen-activated protein kinase pathways by the plasma membrane Na+/H+ exchanger, NHE1. Arch Biochem Biophys, 462(2):195-201

Hoffmann EK, Lambert, IH, Pedersen, SF. 2007. Mechanisms and physiology of cell volume regulation in vertebrates. Physiological Reviews, accepted after revision

Pedersen, S.F., King, S.A., Rigor, R.R., Zhuang, Z., Warren, J.M., and Cala, P.M. 2003. Molecular cloning of NHE1 from Winter flounder RBCs: activation by osmotic shrinkage, cAMP, and calyculin A. Am. J. Physiol. 284:C1561-C1576

Holt, M.E.V., King, S.A, Cala,P.M., and Pedersen, S.F. 2006. Regulation of the Pleuronectes Americanus Na+/H+ exchanger, paNHE1, by osmotic shrinkage, b-adrenergic stimuli, and inhibition of Ser/Thr protein phosphatases. Cell Biochem Biophys, 45(1):1-18

Rentsch ML, Ossum CG, Hoffmann EK, Pedersen SF. 2007. Roles of the Na+/H+ exchanger, NHE1, in regulation of p38 mitogen activated protein kinase and cell death after chemical anoxia in NIH3T3 fibroblasts. Eur J Physiol. 454(4):649-62

Pedersen SF, King SA, Nygaard EB, Rigor RR, Cala PM. 2007. NHE1 inhibition by amiloride- and benzoyl guanidine-type compounds: Inhibitor binding loci deduced from chimeras of NHE1 homologues with endogenous differences in inhibitor sensitivity. J. Biol. Chem. 282(27):19716-27

Pedersen SF, Darborg BV, Rasmussen M, Nylandsted J, Hoffmann EK. 2007. The Na+/H+ exchanger, NHE1, differentially regulates mitogen-activated protein kinase subfamilies after osmotic shrinkage in Ehrlich Lettre Ascites cells. Cell Physiol Biochem, 20(6):735-750

Rasmussen M, Alexander RT, Darborg BV, Møbjerg N, Hoffmann EK, Kapus A, Pedersen SF. 2007. Osmotic cell shrinkage activates ezrin/radixin/moesin (ERM) proteins: Activation mechanisms and physiological implications. Am. J. Physiol. 294(1):C197-212

Schneider L, Stock CM ,Dieterich P, Satir P, Schwab A, Christensen ST, Pedersen SF. 2008. The Na+/H+ exchanger, NHE1, plays a central role in directed fibroblast migration stimulated by PDGFRa signalling in the primary cilium. J. Cell Biol., submitted