Several important themes are addressed: (1) structure-function relationships of the exchanger; (2) regulation of the exchanger; (3) Na/Ca exchanger gene regulation; (4) cellular location and targeting of the exchanger; (5) NC(K)X and PMCA KO mice; (6) Na/Ca exchanger interactions with other proteins; (7) Na/Ca exchange in cardiac function; (8) Na/Ca exchange in neuronal function; (9) Ca2+-extruding mechanisms and apoptosis; (10) Na/Ca exchange in smooth muscle, kidney, and endocrine function; (11) Na/Ca exchange inhibitors: therapeutic opportunities. Experts in the field of the plasma membrane Ca2+-ATPase (PMCA) have also contributed.
The rate of progress in this field has been rapidly increasing, and new concepts have emerged regarding the relation between molecular structure and physiological function. New ideas on physiological modes of regulation have been increasingly testable through the use of transgenic animal models.
This volume and the conference that preceded it continue the tradition of sharing information to fuel new advances in this exciting and important area of research.
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Historical Note Regarding the Discovery of the Na/Ca Exchanger and the PMCA: Andre Herchuelz.
Part I: Structure–Function Relationships of the Exchanger:.
1. What We Know about the Structure of NCX1 and How It Relates to Its Function: Debora A. Nicoll, Xiaoyan Ren, Michela Ottolia, Martin Phillips, Alfredo R. Paredes, Jeff Abramson, and Kenneth D. Philipson.
2. Structural Basis for Ca2+ Regulation in the Na+/Ca2+ Exchanger: Mark Hilge, Jan Aelen, Anastassis Perrakis, and Andgeerten W. Vuister.
3. Structure–Function Relationships of the NCKX2 Na+/Ca2+-K+ Exchanger: Y. Shibukawa, K.J. Kang, T.G. Kinjo, R.T. Szerencsei, H.F. Altimimi, P. Pratikhya, R.J. Winkfein, and P.P.M. Schnetkamp.
4. Examining Ca2+ Extrusion of Na+/Ca2+-K+ Exchangers: Haider F. Altimimi and Paul P.M. Schnetkamp.
5. Topologic Investigation of the NCKX2 Na+/Ca2+-K+ Exchanger α-Repeats: Tashi G. Kinjo, Robert T. Szerencsei, and Paul P.M. Schnetkamp.
6. Transmembrane Segments I, II, and VI of the Canine Cardiac Na+/Ca2+ Exchanger Are in Proximity: Xiaoyan Ren, Debora A. Nicoll, and Kenneth D. Philipson.
7. Effect of Ca2+ on Protein Kinase A-Mediated Phosphorylation of a Specific Serine Residue in an Expressed Peptide Containing the Ca2+-Regulatory Domain of Scallop Muscle Na+/Ca2+ Exchanger: C. Ryan, G. Shaw, and P.M.D. Hardwicke.
Part II. Regulation of the Exchanger:.
8. Regulation of the Cardiac Na+/Ca2+ Exchanger by Calcineurin and Protein Kinase C: Munekazu Shigekawa, Yuki Katanosaka, and Andshigeo Wakabayashi.
9. New Modes of Exchanger Regulation: Physiological Implications: John P. Reeves, Madalina Condrescu, Jason Urbanczyk, and Olga Chernysh.
10. Shedding Light on the Na+/Ca2+ Exchanger: Michela Ottolia, Scott John, Yi Xie, Xiaoyan Ren, and Kenneth D. Philipson.
11. The Regulation of the Na/Ca Exchanger and Plasmalemmal Ca2+ ATPase by Other Proteins: Abdul M. Ruknudin and Edward G. Lakatta.
12. Phosphorylation and Other Conundrums of Na/Ca Exchanger, NCX1: Abdul M. Ruknudin, Shao-Kui Wei, Mark C. Haigney, W.J. Lederer, and Dan H. Schulze.
13. Regulation of Cardiac Na+/Ca2+ Exchanger by Phospholemman: Joseph Y. Cheung, Lawrence I. Rothblum, J. Randall Moorman, Amy L. Tucker, Jianliang Song, Belinda A. Ahlers, Lois L. Carl, Ju Fang Wang, and Xue-Qian Zhang.
14. The Squid Preparation as a General Model for Ionic and Metabolic Na+/Ca2+ Exchange Interactions: Physiopathological Implications: R. Dipolo and L. Beauge.
15. Some Biochemical Properties of the Upregulation of the Squid Nerve Na+/Ca2+ Exchanger by MgATP and Phosphoarginine: Graciela Berberian, Reinaldo Dipolo, and Luis Beauge.
16. Ionic Selectivity of NCKX2, NCKX3, and NCKX4 for Monovalent Cations at K+-Binding Site: Ju-Young Lee, Won-Kyung Ho, and Suk-Ho Lee.
17. In Bovine Heart Na+/Ca2+ Exchanger Maximal Ca2+ i Affinity Requires Simultaneously High pHi and PtdIns-4,5-P2 Binding to the Carrier: Velia Posada, Luis Beauge, and Graciela Berberian.
18. NCX Current in the Murine Embryonic Heart: Development-Dependent Regulation by Na+: Michael Reppel, Hannes Reuter, Philipp Sasse, Jurgen Hescheler, and Bernd K. Fleischmann.
19. Gender Differences in Na/Ca Exchanger Current and β-Adrenergic Responsiveness in Heart Failure in Pig Myocytes: Shao-Kui Wei, John M. McCurley, Stephen U. Hanlon, and Mark C.P. Haigney.
20. Roles of NCX and PMCA in Basolateral Calcium Export Associated with Mineralization Cycles and Cold Acclimation in Crayfish: M.G. Wheatly, Y. Gao, L.M. Stiner, D.R. Whalen, M. Nade, F. Vigo, and A.E. Golshani.
Part III: Na/Ca Exchanger Gene Regulation:.
21. Modulation Pathways of NCX mRNA Stability: Involvement of RhoB: Sachiko Maeda, Isao Matsuoka, and Junko Kimura.
22. Regulation of Ncx1 Gene Expression in the Normal and Hypertrophic Heart: Donald R. Menick, Ludivine Renaud, Avery Buchholz, Joachim G. Muller, Hongming Zhou, Christiana S. Kappler, Steven W. Kubalak, Simon J. Conway, and Lin Xu.
23. Cyclosporin A-Dependent Downregulation of the Na+/Ca2+ Exchanger Expression: H. Rahamimoff, B. Elbaz, A. Alperovich, C. Kimchi-Sarfaty, M.M. Gottesman, Y. Lichtenstein, M. Eskin-Shwartz, and J. Kasir.
Part IV: Cellular Location of the Exchanger:.
24. Functional Significance of Na+/Ca2+ Exchangers Co-localization with Ryanodine Receptors: Anna A. Sher, Robert Hinch, Penelope J. Noble, David J. Gavaghan and Denis Noble.
25. Three Types of Muscles Express Three Sodium–Calcium Exchanger Isoforms: Dmitri O. Levitsky.
Part V: Structure–Function Relationship of the Plasma Membrane Ca2+-ATPase:.
26. Plasma Membrane Ca2+ ATPases as Dynamic Regulators of Cellular Calcium Handling: Emanuel E. Strehler, Ariel J. Caride, Adelaida G. Filoteo, Yuning Xiong, John T. Penniston, and Agnes Enyedi.
27. Functional Specificity of PMCA Isoforms?: Teuta Domi, Francesca Di Leva, Laura Fedrizzi, Alessandro Rimessi, and Marisa Brini.
28. Plasma Membrane Calcium ATPase and Its Relationship to Nitric Oxide Signaling in the Heart: Elizabeth J. Cartwright, Delvac Oceandy, and Ludwig Neyses.
29. Functional Importance of PMCA Isoforms in Growth and Development of PC12 Cells: Ludmila Zylinska, Anna Kozaczuk, Janusz Szemraj, Christos Kargas, and Iwona Kowalska.
Part VI: NC(K)X and PMCA KO Mice:.
30. Na+/Ca2+ Exchanger Knockout Mice: Plasticity of Cardiac Excitation–Contraction Coupling: Christian Pott, Scott A. Henderson, Joshua I. Goldhaber, and Kenneth D. Philipson.
31. Distinct Phenotypes among Plasma Membrane Ca2+-ATPase Knockout Mice: Vikram Prasad, Gbolahan Okunade, Li Liu, Richard J. Paul, and Gary E. Shull.
32. Role of Plasma Membrane Calcium ATPase Isoform 2 in Neuronal Function in the Cerebellum and Spinal Cord: Michael P. Kurnellas, Amanda K. Lee, Karolynn Szczepanowski, and Stella Elkabes.
33. Increased Tolerance to Ischemic Neuronal Damage by Knockdown of Na+–Ca2+ Exchanger Isoform 1: Jing Luo, Yanping Wang, Xinzhi Chen, Hai Chen, Douglas B. Kintner, Gary E. Shull, Kenneth D. Philipson, and Dandan Sun.
34. Resistance of Cardiac Cells to NCX Knockout: A Model Study: Denis Noble, Nobuaki Sarai, Penelope J. Noble, Tsutomu Kobayashi, Satoshi Matsuoka, and Akinori Noma.
35. Homozygous Overexpression of the Na+–Ca2+ Exchanger in Mice: Evidence for Increased Transsarcolemmal Ca2+ Fluxes: Christian Pott, Joshua I. Goldhaber, and Kenneth D. Philipson.
Part VII. Cardiac Function:.
36. Na/Ca Exchange: Regulator of Intracellular Calcium and Source of Arrhythmias in the Heart: L.A. Venetucci, A.W. Trafford, S.C. O’Neill, and D.A. Eisner.
37. Na:Ca Stoichiometry and Cytosolic Ca-Dependent Activation of NCX in Intact Cardiomyocytes: Donald M. Bers and Kenneth S. Ginsburg.
38. Na/Ca Exchange and Cardiac Ventricular Arrhythmias: Karin R. Sipido, V. Bito, G. Antoons, Paul G. Volders, and Marc A. Vos.
39. The Role of the Cardiac Na+/Ca2+ Exchanger in Reverse Remodeling: Relevance for LVAD–Recovery: Cesare M.N. Terracciano, Maren U. Koban, Gopal K. Soppa, Urszula Siedlecka, Joon Lee, Mark A. Stagg, and Magdi H. Yacoub.
40. Regulation of Na+/Ca2+ Exchange Current in the Normal and Failing Heart: Michael Reppel, Bernd K. Fleischmann, Hannes Reuter, Frank Pillekamp, Heribert Schunkert, and Jurgen Hescheler.
41. Phosphorylation of Na+/Ca2+ Exchanger in TAB-Induced Cardiac Hypertrophy: Yuki Katanosaka, Bongju Kim, Shigeo Wakabayashi, Satoshi Matsuoka, And Munekazu Shigekawa.
42. Role of Ca2+ Transporters and Channels in the Cardiac Cell Volume Regulation: A. Takeuchi, S. Tatsumi, N. Sarai, K. Terashima, S. Matsuoka, and A. Noma.
Part VIII: NCX and PMCA in Neuronal and Smooth Muscle Function:.
43. NCX and NCKX Operation in Ischemic Neurons: Lech Kiedrowski.
44. Na+/Ca2+ Exchange and Ca2+ Homeostasis in Axon Terminals of Mammalian Central Neurons: Suk-Ho Lee, Myoung-Hwan Kim, Ju-Young Lee, Sang Hun Lee, Doyun Lee, Kyeong Han Park, and Won-Kyung Ho.
45. ncx1, ncx2, and ncx3 Gene Product Expression and Function in Neuronal Anoxia and Brain Ischemia: L. Annunziato, G. Pignataro, F. Boscia, R. Sirabella, L. Formisano, M. Saggese, O. Cuomo, R. Gala, A. Secondo, D. Viggiano, P. Molinaro, V. Valsecchi, A. Tortiglione, A. Adornetto, A. Scorziello, M. Cataldi, and G.F. Di Renzo.
46. Sodium–Calcium Exchanger in Pulmonary Artery Smooth Muscle Cells: Yun-Min Zheng and Yong-Xiao Wang.
47. Rapid Downregulation of NCX and PMCA in Hippocampal Neurons Following H2O2 Oxidative Stress: Sertac N. Kip and Emanuel E. Strehler.
Part IX: Ca2+ Extruding Mechanisms and Apoptosis:.
48. Cleavage of the Plasma Membrane Ca2+ATPase during Apoptosis: Katalin Paszty, Geza Antalffy, Luca Hegedus, Rita Padanyi, Alan R. Penheiter, Adelaida G. Filoteo, John T. Penniston, and Agnes Enyedi.
49. The Plasma Membrane Na+/Ca2+ Exchanger Is Cleaved by Distinct Protease Families in Neuronal Cell Death: D. Bano, E. Munarriz, H.L. Chen, E. Ziviani, G. Lippi, K.W. Young, and P. Nicotera.
50. Role of Na/Ca Exchange and the Plasma Membrane Ca2+–ATPase in β Cell Function and Death: Andre Herchuelz, Adama Kamagate, Helena Ximenes, and Francoise Van Eylen.
51. Overexpression of Na/Ca Exchanger Reduces Viability and Proliferation of Gliosarcoma Cells: Evrard Nguidjoe and Andre Herchuelz.
52. Redox Modulation of the Apoptogenic Activity of Thapsigargin: Claudia Cerella, Simona Coppola, Maria D'Alessio, Milena De Nicola, Andrea Magrini, Antonio Bergamaschi, and Lina Ghibelli.
53. The Role of Na+/Ca+ Exchanger in Endothelin-1-Aggravated Hypoxia/Reoxygenation-Induced Injury in Renal Epithelial Cells: Satomi Kita, Ayako Furuta, Yukio Takano, and Takahiro Iwamoto.
54. Involvement of Na+/Ca2+ Exchanger Type-1 in Ischemia-Induced Neovascularization in the Mouse Hindlimb: Yukiko Matsui, Satomi Kita, Takeshi Katsuragi, Issei Komuro, Takahiro Iwamoto, and Hiroyuki Ohjimi.
55. The Na+/Ca2+ Exchanger Isoform 3 (NCX3) but Not Isoform 2 (NCX2) and 1 (NCX1) Singly Transfected in BHK Cells Plays a Protective Role in a Model of in Vitro Hypoxia: Agnese Secondo, Ilaria Rosaria Staiano, Antonella Scorziello, Rossana Sirabella, Francesca Boscia, Annagrazia Adornetto, Lorella Maria Teresa Canzoniero, Gianfranco Di Renzo, and Lucio Annunziato.
56. Involvement of the Potassium-Dependent Sodium/Calcium Exchanger Gene Product NCKX2 in the Brain Insult Induced by Permanent Focal Cerebral Ischemia: Ornella Cuomo, Giuseppe Pignataro, Rosaria Gala, Francesca Boscia, Anna Tortiglione, Pasquale Molinaro, Gianfranco Di Renzo, Jonathan Lytton, Andlucio Annunziato.
Part X: Na/Ca Exchange in the Endoplasmic Reticulum, the Mitochondria, and the Nuclear Envelope:.
57. Analysis of Calcium Changes in Endoplasmic Reticulum during Apoptosis by the Fluorescent Indicator Chlortetracycline: Claudia Cerella, Cristina Mearelli, Milena De Nicola, Maria D'Alessio, Andrea Magrini, Antonio Bergamaschi, and Lina Ghibelli.
58. Sodium–Calcium Exchangers in the Nucleus: An Unexpected Locus and an Unusual Regulatory Mechanism: Robert W. Ledeen and Gusheng Wu.
59. Mitochondrial Ca2+ Flux through Na+/Ca2+ Exchange: Bongju Kim and Satoshi Matsuoka.
60. Non-apoptogenic Ca2+-Related Extrusion of Mitochondria in Anoxia/Reoxygenation Stress: Annalisa Dorio, Claudia Cerella, Milena De Nicola, Maria D'Alessio, Giampiero Gualandi, and Lina Ghibelli.
Part XI. Na/Ca Exchange Inhibitors: Therapeutic Opportunities:.
61. Na+/Ca2+ Exchange as a Drug Target - Insights from Molecular Pharmacology and Genetic Engineering: Takahiro Iwamoto.
62. Inhibitory Mechanism of SN-6, A Novel Benzyloxyphenyl Na+/Ca2+ Exchange Inhibitor: Satomi Kita and Takahiro Iwamoto.
63. Electrophysiological Effects of SN-6, a Novel Na+/Ca2+ Exchange Inhibitor on Membrane Currents in Guinea Pig Ventricular Myocytes: Chun-Feng Niu, Yasuhide Watanabe, Takahiro Iwamoto, Kanna Yamashita, Hiroshi Satoh, Tuyoshi Urushida, Hideharu Hayashi, and Junko Kimura.
64. Directionality in Drug Action on Sodium–Calcium Exchange: D. Noble And M. P. Blaustein.
Index of Contributors
Mordecai P. Blaustein University of Maryland School of Medicine, Baltimore.
Jonathan Lytton University of Calgary.
Kenneth D. Philipson UCLA School of Medicine.