Browse > Article

Structure-Activity Relationships of Dimethylsphingosine (DMS) Derivatives and their Effects on Intracellular pH and $Ca^{2+}$ in the U937 Monocyte Cell Line  

Chang, Young-Ja (Laboratory of Pharmacology, College of Pharmacy and Research Institute for Drug Development, Pusan National University)
Lee, Yun-Kyung (Laboratory of Pharmacology, College of Pharmacy and Research Institute for Drug Development, Pusan National University)
Lee, Eun-Hee (Laboratory of Pharmacology, College of Pharmacy and Research Institute for Drug Development, Pusan National University)
Park, Jeong-Ju (Division of Molecular Life Sciences, Pohang University of Sciecne and Technology)
Chung, Sung-Kee (Division of Molecular Life Sciences, Pohang University of Sciecne and Technology)
Im, Dong-Soon (Laboratory of Pharmacology, College of Pharmacy and Research Institute for Drug Development, Pusan National University)
Publication Information
Archives of Pharmacal Research / v.29, no.8, 2006 , pp. 657-665 More about this Journal
Abstract
We recently reported that dimethylsphingosine (DMS), a metabolite of sphingolipids, increased intracellular pH and $Ca^{2+}$ concentration in U937 human monocytes. In the present study, we found that dimethylphytosphingosine (DMPH) induced the above responses more robustly than DMS. However, phytosphingosine, monomethylphytosphingosine or trimethylsphingosine showed little or no activity. Synthetic C3 deoxy analogues of sphingosine did show similar activities, with the C16 analogue more so than C18. The following structure-activity relationships were observed between DMS derivatives and the intracellular pH and $Ca^{2+}$ concentrations in U937 monocytes; 1) dimethyl modification is important for the DMS-induced increase of intracellular pH and $Ca^{2+}$, 2) the addition of an OH group on C4 enhances both activities, 3) the deletion of the OH group on C3 has a negligible effect on the activities, and 4) C16 appears to be more effective than C18. We also found that W-7, a calmodulin inhibitor, blocked the DMS-induced pH increase, whereas, KN-62, ML9, and MMPX, specific inhibitors for calmodulin-dependent kinase II, myosin light chain kinase, and $Ca^{2+}$-calmodulin-dependent phosphodiesterase, respectively, did not affect DMS-induced increases of pH in the U937 monocytes.
Keywords
Dimethylsphingosine; pH; Sphingosine; Calcium; Structure-activity relationship;
Citations & Related Records

Times Cited By Web Of Science : 10  (Related Records In Web of Science)
Times Cited By SCOPUS : 10
연도 인용수 순위
1 Igarashi, Y., Hakomori, S., Toyokuni, T., Dean, B., Fujita, S., Sugimoto, M., Ogawa, T., el-Ghendy, K., and Racker, E., Effect of chemically well-defined sphingosine and its Nmethyl derivatives on protein kinase C and src kinase activities. Biochemistry, 28, 6796-6800 (1989)   DOI   ScienceOn
2 James-Kracke, M. R., Quick and accurate method to convert BCECF fluorescence to pHi: calibration in three different types of cell preparations. J. Cell. Physiol., 151, 596-603 (1992)   DOI
3 Merrill, A. H., Jr., Nimkar, S., Menaldino, D., Hannun, Y. A., Loomis, C., Bell, R. M., Tyagi, S. R., Lambeth, J. D., Stevens, V. L., Hunter, R., Structural requirements for long-chain (sphingoid) base inhibition of protein kinase C in vitro and for the cellular effects of these compounds. Biochemistry, 28, 3138-3145 (1989)   DOI   ScienceOn
4 Putney, L. K. and Barber, D. L., Na-H exchange-dependent increase in intracellular pH times G2/M entry and transition. J. Biol. Chem., 278, 44645-44649 (2003)   DOI   ScienceOn
5 Kimura, S., Kawa, S., Ruan, F., Nisar, M., Sadahira, Y., Hakomori, S., and Igarashi, Y., Effect of sphingosine and its N-methyl derivatives on oxidative burst, phagokinetic activity, and trans-endothelial migration of human neutrophils. Biochem. Pharmacol., 44, 1585-1595 (1992)   DOI   ScienceOn
6 Alfonso, A., De la Rosa, L. A., Vieytes, M. R., and Botana, L. M., Dimethylsphingosine increases cytosolic calcium and intracellular pH in human T lymphocytes. Biochem. Pharmacol., 65, 465-478 (2003)   DOI   ScienceOn
7 Lee, E. H., Lee, Y. K., Im, Y. J., Kim, J. H., Okajima, F., and Im, D. S., Dimethylsphingosine regulates intracellular pH and $Ca^{2+}$ in human monocytes. J. Pharmacol. Sci., 100, 289-296 (2006)   DOI   ScienceOn
8 Endo, K., Igarashi, Y., Nisar, M., Zhou, Q. H., and Hakomori, S., Cell membrane signaling as target in cancer therapy: inhibitory effect of N,N-dimethyl and N,N,N-trimethyl sphingosine derivatives on in vitro and in vivo growth of human tumor cells in nude mice. Cancer Res., 51, 1613- 1618 (1991)
9 Izumi, H., Torigoe, T., Ishiguchi, H., Uramoto, H., Yoshida, Y., Tanabe, M., Ise, T., Murakami, T., Yoshida, T., Nomoto, M., and Kohno, K., Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy. Cancer Treat. Rev., 29, 541-549 (2003)   DOI   ScienceOn
10 Himmel, H. M., Meyer zu Heringdorf, D., Windorfer, B., van Koppen, C. J., Ravens, U., and Jakobs, K. H., Guanine nucleotide-sensitive inhibition of L-type $Ca^{2+}$ current by lysosphingolipids in RINm5F insulinoma cells. Mol. Pharmacol., 53, 862-869 (1998)
11 De Jonghe, S., Van Overmeire, I., Poulton, S., Hendrix, C., Busson, R., Van Calenbergh, S., De Keukeleire, D., Spiegel, S., and Herdewijn, P., Structure-activity relationship of shortchain sphingoid bases as inhibitors of sphingosine kinase. Bioorg. Med. Chem. Lett., 9, 3175-3180 (1999)   DOI   ScienceOn
12 Thomas, J. A., Buchsbaum, R. N., Zimniak, A., and Racker, E., Intracellular pH measurements in Ehrlich ascites tumor cells utilizing spectroscopic probes generated in situ. Biochemistry, 18, 2210-2218 (1979)   DOI   ScienceOn
13 Mano, N., Oda, Y., Yamada, K., Asakawa, N., and Katayama, K., Simultaneous quantitative determination method for sphingolipid metabolites by liquid chromatography/ionspray ionization tandem mass spectrometry. Anal. Biochem., 244, 291-300 (1997)   DOI   ScienceOn
14 Merrill, A. H., Jr., Wang, E., Mullins, R. E., Jamison, W. C., Nimkar, S., and Liotta, D. C., Quantitation of free sphingosine in liver by high-performance liquid chromatography. Anal. Biochem., 171, 373-381 (1988)   DOI   ScienceOn
15 Igarashi, Y. and Hakomori, S., Enzymatic synthesis of N,Ndimethyl- sphingosine: demonstration of the sphingosine: Nmethyltransferase in mouse brain. Biochem. Biophys. Res. Commun., 164, 1411-1416 (1989)   DOI   ScienceOn
16 Hannun, Y. A. and Bell, R. M., Lysosphingolipids inhibit protein kinase C: implications for the sphingolipidoses. Science, 235, 670-674 (1987)   DOI
17 Lim, H. S., Park, J. J., Ko, K., Lee, M. H., and Chung, S. K., Syntheses of sphingosine-1-phosphate analogues and their interaction with EDG/S1P receptors. Bioorg. Med. Chem. Lett., 14, 2499-2503 (2004)   DOI   ScienceOn
18 Okoshi, H., Hakomori, S., Nisar, M., Zhou, Q. H., Kimura, S., Tashiro, K., and Igarashi, Y., Cell membrane signaling as target in cancer therapy. II: Inhibitory effect of N,N,Ntrimethylsphingosine on metastatic potential of murine B16 melanoma cell line through blocking of tumor cell-dependent platelet aggregation. Cancer Res., 51, 6019-6024 (1991)
19 Edsall, L. C., Van Brocklyn, J. R., Cuvillier, O., Kleuser, B., and Spiegel, S., N,N-Dimethylsphingosine is a potent competitive inhibitor of sphingosine kinase but not of protein kinase C: modulation of cellular levels of sphingosine 1-phosphate and ceramide. Biochemistry, 37, 12892-12898 (1998)   DOI   ScienceOn
20 Yun, M. R., Okajima, F., and Im, D. S., The action mode of lysophosphatidylcholine in human monocytes. J. Pharmacol. Sci., 94, 45-50 (2004)   DOI   ScienceOn
21 Lipskaia, L. and Lompre, A. M., Alteration in temporal kinetics of $Ca^{2+}$ signaling and control of growth and proliferation. Biol. Cell, 96, 55-68 (2004)   DOI   ScienceOn