A complex signaling cascade links the serotonin2A receptor to phospholipase A2 activation: the involvement of MAP kinases

J Neurochem. 2003 Aug;86(4):980-91. doi: 10.1046/j.1471-4159.2003.01921.x.


Previous studies in our laboratory have shown that in NIH3T3-5HT2A cells, 5-HT-induced AA release is PLA2-coupled and independent of 5-HT2A receptor-mediated PLC activation. Although 5-HT2A receptor-mediated PLC activation is known to be Galphaq-coupled, much less is understood about 5-HT2A receptor-mediated PLA2 activation. Therefore, the studies presented here were aimed at elucidating the signal transduction pathway linking stimulation of the 5-HT2A receptor to PLA2 activation. By employing various selective inhibitors, toxins, and antagonistic peptide constructs, we propose that the 5-HT2A receptor can couple to PLA2 activation through two parallel signaling cascades. Initial experiments were designed to examine the role of pertussis toxin-sensitive G proteins, namely Galphai/o, as well as pertussis toxin-insensitive G proteins, namely Galpha12/13, in 5-HT-induced AA release. Furthermore, inactivation of both Gbetagamma heterodimers and Rho proteins resulted in decreased agonist-induced AA release, without having any effect on PLC-IP accumulation. We also demonstrated 5-HT2A receptor-mediated phosphorylation of ERK1,2 and p38. Moreover, pretreatment with selective ERK1,2 and p38 inhibitors resulted in decreased 5-HT-induced AA release. Taken together, these results suggest that the 5-HT2A receptor expressed in NIH3T3 cells can couple to PLA2 activation though a complex signaling mechanism involving both Galphai/o-associated Gbetagamma-mediated ERK1,2 activation and Galpha12/13-coupled, Rho-mediated p38 activation.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Animals
  • Arachidonic Acid / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Activators / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • GTP-Binding Proteins / antagonists & inhibitors
  • GTP-Binding Proteins / metabolism
  • Inositol Phosphates / metabolism
  • MAP Kinase Signaling System / physiology*
  • Mice
  • Mitogen-Activated Protein Kinase 1 / drug effects
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / metabolism
  • Phospholipases A / metabolism*
  • Phospholipases A2
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Serotonin / genetics
  • Receptors, Serotonin / metabolism*
  • Signal Transduction / physiology*
  • Type C Phospholipases / metabolism
  • p38 Mitogen-Activated Protein Kinases
  • rho GTP-Binding Proteins / antagonists & inhibitors
  • rho GTP-Binding Proteins / metabolism


  • Enzyme Activators
  • Enzyme Inhibitors
  • Inositol Phosphates
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Serotonin
  • Arachidonic Acid
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Phospholipases A
  • Phospholipases A2
  • Type C Phospholipases
  • GTP-Binding Proteins
  • rho GTP-Binding Proteins