Kenneth Philipson

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Work Titles
UCLA Professor, Physiology Faculty, Cardiovascular Research Laboratory Faculty, Cardiology

Contact Information:

Email Address:

kphilipson@mednet.ucla.edu


Work Phone Number:

310-794-7103

310-825-7679

Work Address:

Laboratory
MRL
Los Angeles, CA 90095

Office
MRL
Los Angeles, CA 90095


Detailed Biography:

Cardiac Sodium-Calcium Exchange Ca2+ transport across the plasma membrane (sarcolemma) of cardiac muscle cells regulates the strength of cardiac contraction. My laboratory primarily studies an important sarcolemmal transport system: Na+-Ca2+ exchange. This transporter catalyzes the exchange of 3 Na+ ions on one side of the membrane for 1 Ca2+ ion on the other side and regulates cardiac contractility. Several aspects of the Na+-Ca2+ exchange system are being investigated. These include structure-function studies, regulatory studies, expression studies of different isoforms and physiological studies using transgenic mice. To begin to understand the transport mechanism of the Na+-Ca2+ exchange protein, we have isolated and cloned the exchange protein. Site-directed mutagenesis studies are in progress. Mutants are analyzed electrophysiologically using a novel giant excised patch technique. We are also analyzing regulatory properties of the cardiac Na+-Ca2+ exchanger. 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 now defining this site at the molecular level. 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.

Publications:

A selected list of publications:

Ottolia, M., John, S., Ren, X. and Philipson, K.D.   Fluorescent Na+-Ca2+ exchangers: electrophysiological and optical characterization, J. Biol. Chem, 2007; 282: 3695-3701.
Cavalli, A., Eghbali, M., Minosyan, T.Y., Stefani, E. and Philipson, K.D.   Localization of sarcolemmal proteins to lipid rafts in the myocardium, Cell Calcium, 2007; 42: 313-322.
Pott, C., Ren, X., Tran, D.X., Yang, M.-J., Henderson, S., Jordan, M.C., Roos, K.P., Garfinkel, A., Philipson, K.D. and Goldhaber, J.I.   Mechanism of shortened action potential duration in Na+-Ca2+ exchanger knockout mice, Am. J. Physiol, 2007; 292: C968-C973.
Pott, C., Yip, M., Goldhaber, J.I. and Philipson, K.D.   Regulation of cardiac L-type Ca2+ current in Na+-Ca2+ exchanger knockout mice: functional coupling of the Ca2+ channel and the Na+-Ca2+ exchanger. , Biophys. J, 2007; 92: 1431-1437.
Besserer, G.M., Ottolia, M., Nicoll, D.A., Chaptal, V., Cascio, D., Philipson, K.D. and Abramson, J.   The second Ca2+-binding domain of the Na+-Ca2+ exchanger is essential for regulation: Crystal structures and mutational analysis, Proc. Natl. Acad. Sci, 2007; 104: 18467-18472.
Ottolia, M., Philipson, K.D. and John, S.   Xenopus oocyte plasma membrane sheets for FRET analysis, Am. J. Physiol, 2007; 292: C1519-C1522.
Ren, X., Nicoll, D.A. and Philipson, K.D.   Helix packing of the cardiac Na+-Ca2+ exchanger: proximity of transmembrane segments 1, 2 and 6. J. Biol. Chem. 281:22808-22814, 2006, J. Biol. Chem, 2006; 281: 22808-22814.
Nicoll, D.A., Sawaya, M., Kwon, S., Cascio, D., Philipson, K.D. and Abramson, J.   The crystal structure of the primary Ca2+ sensor of the Na+/Ca2+ exchanger reveals a novel Ca2+ binding motif. , J. Biol. Chem, 2006; 281: 21577-21581.
Pott, C.H., Philipson, K.D. and Goldhaber, J.I.   Excitation-contraction coupling in Na+-Ca2+ exchanger knockout mice: reduced transsarcolemmal Ca2+ flux. , Circ. Res, 2005; 97: 1288-1295.
Ottolia, M., Nicoll, D.A. and Philipson, K.D.   Mutational analysis of the a-1 repeat of the cardiac Na+-Ca2+ exchanger , J. Biol. Chem, 2005; 280: 1061-1069.
Henderson, SA Goldhaber, JI So, JM Han, T Motter, C Ngo, A Chantawansri, C Ritter, MR Friedlander, M Nicoll, DA Frank, JS Jordan, MC Roos, KP Ross, RS Philipson, KD   Functional adult myocardium in the absence of Na+-Ca2+ exchange: cardiac-specific knockout of NCX1 Circulation research. , 2004; 95(6): 604-11.
Ottolia, M., Philipson, K.D. and John, S.   Conformational changes of the Ca2+ regulatory site of the Na+-Ca2+ exchanger detected by FRET, Biophys. J, 2004; 87: 899-906.
Reuter, H Han, T Motter, C Philipson, KD Goldhaber, JI   Mice overexpressing the cardiac sodium-calcium exchanger: defects in excitation-contraction coupling The Journal of physiology. , 2004; 554(Pt 3): 779-89.
Reuter, H Henderson, SA Han, T Mottino, GA Frank, JS Ross, RS Goldhaber, JI Philipson, KD   Cardiac excitation-contraction coupling in the absence of Na(+) - Ca2+ exchange Cell calcium. , 2003; 34(1): 19-26.
Reuter, H Henderson, SA Han, T Matsuda, T Baba, A Ross, RS Goldhaber, JI Philipson, KD   Knockout mice for pharmacological screening: testing the specificity of Na+-Ca2+ exchange inhibitors Circulation research. , 2002; 91(2): 90-2.
Reuter, H Henderson, SA Han, T Ross, RS Goldhaber, JI Philipson, KD   The Na+-Ca2+ exchanger is essential for the action of cardiac glycosides Circulation research. , 2002; 90(3): 305-8.
Philipson, KD Gallivan, JP Brandt, GS Dougherty, DA Lester, HA   Incorporation of caged cysteine and caged tyrosine into a transmembrane segment of the nicotinic ACh receptor American journal of physiology. Cell physiology. , 2001; 281(1): C195-206.
Qiu, Z., Nicoll, D.A. and Philipson, K.D.   Helix packing of functionally important regions of the cardiac Na+-Ca2+ exchanger, J. Biol. Chem. , 2001; 276: 194-199.
Kraev, A., Quednau, B.D., Leach, S., Li, X.-F., Dong, H., Winkfein, R., Perizzolo, M., Cai, X., Yang, R., Philipson, K.D. and Lytton, J.   Molecular cloning of a third membere of the potassium-dependent sodium-calcium exchange gene family, NCKX3, J. Biol. Chem, 2001; 276: 23161-23172.
Terracciano, C.M.N., Philipson, K.D. and MacLeod, K.T.   Overexpression of the Na+/Ca2+ exchanger and inhibition of the sarcoplasmic reticulum Ca2+-ATPase in ventricular myocytes from transgenic mice, Cardiovasc. Res, 2001; 49: 38-47.
Ottolia, M John, S Qiu, Z Philipson, KD   Split Na+-Ca2+ exchangers. Implications for function and expression The Journal of biological chemistry. , 2001; 276(22): 19603-9.
Weber, CR Ginsburg, KS Philipson, KD Shannon, TR Bers, DM   Allosteric regulation of Na/Ca exchange current by cytosolic Ca in intact cardiac myocytes The Journal of general physiology. , 2001; 117(2): 119-31.
Hampton, T.G., Wang, J.F., DeAngelis, J., Amende, I., Philipson, K.D. and Morgan, J.P.   Enhanced gene expression of Na+/Ca2+ exchanger attenuates ischemic and hypoxic gene expression, Am. J. Physiol, 2000; 279: H2846-H2854.
Santacruz-Toloza, L., Ottollia, M., Nicoll, D.A., and Philipson, K.D.   Functional Analysis of a Disulfide Bond in the Cardiac Na+-Ca2+ Exchanger, J. Biol. Chem, 2000; 275: 182-188.
Linck, B., Boknik, P., Huke, S., Kirchhefer, U., Knapp, J., Luss, H., Muller, F.U., Neumann, J., Tanriseven, Z., Vahlensieck, U., Baba, H.A., Jones, L.R., Philipson, K.D. and Schmitz, W   Functional properties of transgenic mouse hearts overexpressing both calsequestrin and the Na+-Ca2+ exchanger, J. Pharmacol. Exptl. Therapeut, 2000; 294: 648-657.
Schillinger, W., Janssen, P.M.L., Emami, S., Henderson, S.A., Ross, R.S., Teucher, N., Zeitz, O., Philipson, K.D., Prestle, J. and Hasenfuss, G.   Impaired contractile performance of cultured rabbit ventricular myocytes after adenoviral gene transfer of Na+-Ca2+ exchanger, Circ. Res, 2000; 87: 581-587.
Philipson, KD Nicoll, DA   Sodium-calcium exchange: a molecular perspective Annual review of physiology. , 2000; 62: 111-33.
He, Z Feng, S Tong, Q Hilgemann, DW Philipson, KD   Interaction of PIP(2) with the XIP region of the cardiac Na/Ca exchanger American journal of physiology. Cell physiology. , 2000; 278(4): C661-6.
Maxwell, K Scott, J Omelchenko, A Lukas, A Lu, L Lu, Y Hnatowich, M Philipson, KD Hryshko, LV   Functional role of ionic regulation of Na+/Ca2+ exchange assessed in transgenic mouse hearts The American journal of physiology. , 1999; 277(6 Pt 2): H2212-21.
Nicholas, S.B. and Philipson, K.D.   Cardiac Expression of the Na+/Ca2+ Exchanger NCX1 is GATA Factor Dependent, Am. J. Physiol, 1999; 277: H324-H330.
Ponce-Hornos, J.E., Philipson, K.D., Bonazzola, P., Langer, G.A.   Energetics of Na+-Ca2+ Exchange in Resting Cardiac Muscle, Biophys. J, 1999; 77: 3319-3327.
Nicoll, DA Ottolia, M Lu, L Lu, Y Philipson, KD   A new topological model of the cardiac sarcolemmal Na+-Ca2+ exchanger The Journal of biological chemistry. , 1999; 274(2): 910-7.

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