My research focuses on the regulation of Ca2+ transport across heart cell membranes. Primarily, we focus on a specific transporter,
the Na+-Ca2+ exchanger, important in controlling cardiac contractility. Several aspects of the Na+-Ca2+
exchange system are being investigated.
These include structure-function studies, regulatory studies, and physiological studies using genetically altered mice. Site-directed mutagenesis studies are in progress to determine the ion translocation pathway through the protein. Mutants are analyzed electrophysiologically using a novel giant excised patch technique. In addition to transporting Ca2+, the exchanger is regulated by Ca2+ at a high affinity Ca2+ binding site on the intracellular surface of the exchanger. Studies in progress are defining this site at the molecular and structural level. We also study the physiological and pathophysiological properties of mice with genetically altered levels of the Na+-Ca2+ exchanger. Unique and surprising phenotypes have been obtained. In short, a variety of molecular biological, biochemical and physiological approaches are being utilized to study the function and role of an interesting and important membrane transport system.
Mercado Besserer, G., Nicoll, D.A., Abramson, J. and Philipson, K.D. (2012) Characterization and purification of a Na+/Ca2+ exchanger from an Archaebacterium. J. Biol. Chem. 287:8652-8659,
John, S., Ribalet, B., Weiss, J.N., Philipson, K.D. and Ottolia, M. (2011) Na+-Ca2+ exchanger dimers: Ca2+-dependent interactions detected by FRET. Proc. Natl. Acad. Sci. 108:1699-1704, PMID: 21209335
Larbig, R., Torres, N., Bridge, J.H.B., Goldhaber, J.I. and Philipson, K.D. (2010) Activation of reverse Na+-Ca2+ exchange by the Na+ current augments the cardiac Ca2+ transient: evidence from NCX knockout mice. J. Physiol. 588:3267-3276, PMID: 20643777