Delineation of the role of a Na+/Ca2+ exchanger in regulating intracellular Ca2+ in T cells.
One of the metabolic events that results from ligation of the CD3-TCR is an increase in [Ca2+]i. The mechanisms that generate this rise in [Ca2+]i are poorly understood, but involve mobilization of intracellular Ca2+ stores and the movement of extracellular Ca2+ into the cell. To examine the role of Na+/Ca2+ exchange in the increase in [Ca2+]i after CD3-TCR engagement, the effects of specific inhibitors of Na+/Ca2+ exchange, DCB, CBDMB, and bepridil, were examined. Inhibitors of Na+/Ca2+ exchange suppressed IL2 production and the rise in [Ca2+]i in Jurkat cells stimulated by anti-CD3 mAb. Mobilization of intracellular Ca2+ stores and mitogen-stimulated inositol phosphate production were not inhibited by these agents. Inhibitors of Na+/Ca2+ exchange also inhibited mitogen responses of normal T cells and the sustained increase in [Ca2+]i resulting from cross-linking class I MHC molecules, addition of PHA, or anti-CD3 mAb. Additional evidence for an important role of a Na+/Ca2+ exchanger in generating increases in [Ca2+]i after CD3 ligation was the finding that replacing extracellular Na+ with Li+, that cannot be transported by the Na+/Ca2+ exchanger, nearly abrogated the rise in [Ca2+]i induced by cross-linking CD3. These results are consistent with the conclusion that a Na+/Ca2+ exchanger is important in regulating changes in [Ca2+]i that are critical for T cell activation.
Wacholtz
M C
MC
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235.
Cragoe
E J
EJ
Lipsky
P E
PE
D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015764:Bepridil / Q000494:pharmacology; D017252:CD3 Complex; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000276:immunology*; D002460:Cell Line / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D006801:Humans; D008094:Lithium / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology*; D008938:Mitosis / Q000187:drug effects; D019831:Sodium-Calcium Exchanger; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D002352:Carrier Proteins; D019831:Sodium-Calcium Exchanger; C054391:5-(N-4-chlorobenzyl)-N-(2',4'-dimethyl)benzamil; D015764:Bepridil; D000584:Amiloride; D008094:Lithium; D002118:Calcium