Structure-activity relationships of dimethylsphingosine (DMS) derivatives and their effects on intracellular pH and Ca2+ in the U937 monocyte cell line.
We recently reported that dimethylsphingosine (DMS), a metabolite of sphingolipids, increased intracellular pH and Ca2+ 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 Ca2+ concentrations in U937 monocytes; 1) dimethyl modification is important for the DMS-induced increase of intracellular pH and Ca2+, 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.
Chang
Young-Ja
YJ
Laboratory of Pharmacology, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 609-735, Korea.
Lee
Yun-Kyung
YK
Lee
Eun-Hee
EH
Park
Jeong-Ju
JJ
Chung
Sung-Kee
SK
Im
Dong-Soon
DS
D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002413:Cations, Divalent; D016923:Cell Death / Q000187:drug effects; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D004354:Drug Screening Assays, Antitumor; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D042541:Intracellular Space / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000502:physiology; D020298:U937 Cells
D002147:Calmodulin; D002413:Cations, Divalent; D010726:Phosphodiesterase Inhibitors; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D009219:Myosin-Light-Chain Kinase; D010727:Phosphoric Diester Hydrolases; D010738:Type C Phospholipases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C061800:N,N-dimethylsphingosine; D013110:Sphingosine; D002118:Calcium