Unique properties of the capacitative Ca(2+)-entry antagonist LU 52396: its inhibitory activity depends on the activation state of the cells.
The pharmacological properties of the recently described antagonist for capacitative Ca2+ entry LU 52396 were investigated and compared to known Ca2+ antagonists in Jurkat T-lymphocytes. In the first set of experiments, cells were stimulated with the anti-CD3 monoclonal antibody OKT3 and, subsequently, Ca2+ antagonists were added. Under such conditions SK-F 96365, econazole, nitrendipine and ZnCl2 dose-dependently antagonized Ca2+ signaling, whereas LU 52396 in concentrations up to 100 microM did not. In contrast, when LU 52396 was added a few minutes before OKT3, a dose-dependent inhibition of the OKT3-stimulated Ca2+ signals by LU 52396 was observed. Likewise, by prior addition of LU 52396 to thapsigargin-stimulated Jurkat T cells, a dose-dependent inhibition of Ca2+ signals was achieved. The IC50 value of LU 52396 for both agonists was about 5 microM. LU 52396 also inhibited Jurkat T cell proliferation, but showed cytotoxic effects at concentrations > 50 microM. Our data indicate that, in contrast to the other Ca2+ antagonists SK-F 96365, econazole, nitrendipine and ZnCl2, LU 52396 recognized the channel for capacitative Ca2+ entry only when intracellular Ca2+ was low and the channel was in its closed state.
Guse
A H
AH
Department of Enzyme Chemistry, University of Hamburg, Germany.
de Wit
C
C
Klokow
T
T
Schweitzer
K
K
Mayr
G W
GW
D017252:CD3 Complex; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation; D010879:Piperazines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
D017252:CD3 Complex; D002121:Calcium Channel Blockers; C094080:LU 52396; D010879:Piperazines; D002118:Calcium