Sphingosine prevents diacylglycerol signaling to mitogen-activated protein kinase in airway smooth muscle

D Tolan, A M Conway, N J Pyne, S Pyne

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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 languageEnglish
Pages (from-to)C928-936
Number of pages8
JournalAmerican Journal of Physiology
Volume273
Issue number3
Publication statusPublished - Sep 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

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