Abstract
Because many agonists utilize diacylglycerol (DAG) to initiate nuclear transcriptional activity via protein kinase C (PKC), we have investigated whether sphingosine might counter DAG. Sphingosine inhibited PKC activity in an isolated airway smooth muscle cell lysate and prevented the activation of mitogen-activated protein kinase (MAPK) by platelet-derived growth factor, bradykinin, and phorbol 12-myristate 13-acetate in intact cells. MAPK activation in response to all the agonists involves PKC. The stimulation of [3H]palmitate-labeled cells with sphingosine, in the presence of butan-1-ol (0.3%, vol/vol), induced an increase in [3H]phosphatidate (PtdOH) but was without effect on [3H]DAG. [3H]PtdOH synthesis was inhibited, whereas [3H]DAG levels were increased in the presence of the DAG kinase inhibitor R-59949, indicating that sphingosine stimulates phospholipase C/DAG kinase. Recycling of DAG from PtdOH was prevented by a sphingosine-dependent inhibition of PtdOH phosphohydrolase-2 activity. In conclusion, the sphingosine-induced conversion of DAG to PtdOH may serve to optimize the effect of sphingosine on MAPK. This may account for the antiproliferative action of sphingosine.
Original language | English |
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Pages (from-to) | C928-936 |
Number of pages | 8 |
Journal | American Journal of Physiology |
Volume | 273 |
Issue number | 3 |
Publication status | Published - Sept 1997 |
Keywords
- 1-butanol
- animals
- bradykinin
- butanols
- calcium-calmodulin-dependent protein kinases
- cells, cultured
- diacylglycerol kinase
- diglycerides
- enzyme activation
- enzyme inhibitors
- guinea pigs
- kinetics
- muscle, smooth
- palmitic acid
- phosphatidate phosphatase
- phosphotransferases (alcohol group acceptor)
- piperidines
- platelet-derived growth factor
- protein kinase C
- quinazolines
- quinazolinones
- signal transduction
- sphingosine
- tetradecanoylphorbol acetate
- trachea