Characterization of serotonin 5-HT2C receptor signaling to extracellular signal-regulated kinases 1 and 2

J Neurochem. 2005 Jun;93(6):1603-15. doi: 10.1111/j.1471-4159.2005.03161.x.


Serotonin 5-HT2C receptors (5-HT(2C)Rs) are almost exclusively expressed in the CNS, and implicated in disorders such as obesity, depression, and schizophrenia. The present study investigated the mechanisms governing the coupling of the 5-HT(2C)R to the extracellular signal-regulated kinases (ERKs) 1/2, using a Chinese hamster ovary (CHO) cell line stably expressing the receptor at levels comparable to those found in the brain. Using the non-RNA-edited isoform of the 5-HT(2C)R, constitutive ERK1/2 phosphorylation was observed and found to be modulated by full, partial and inverse agonists. Interestingly, agonist-directed trafficking of receptor stimulus was also observed when comparing effects on phosphoinositide accumulation and intracellular Ca2+ elevation to ERK1/2 phosphorylation, whereby the agonists, [+/-]-2,5-dimethoxy-4-iodoamphetamine (DOI) and quipazine, showed reversal of efficacy between the phosphoinositide/Ca2+ pathways, on the one hand, and the ERK1/2 pathway on the other. Subsequent molecular characterization found that 5-HT-stimulated ERK1/2 phosphorylation in this cellular background requires phospholipase D, protein kinase C, and activation of the Raf/MEK/ERK module, but is independent of both receptor- and non-receptor tyrosine kinases, phospholipase C, phosphoinositide 3-kinase, and endocytosis. Our findings underscore the potential for exploiting pathway-selective receptor states in the differential modulation of signaling pathways that play prominent roles in normal and abnormal neuronal signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Calcium Signaling / physiology
  • Cricetinae
  • Diglycerides / metabolism
  • Endocytosis / physiology
  • Humans
  • Ligands
  • MAP Kinase Signaling System / physiology*
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositols / metabolism
  • Phospholipase D / metabolism
  • Phospholipases A / metabolism
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism
  • Receptor, Serotonin, 5-HT1B / genetics
  • Receptor, Serotonin, 5-HT1B / metabolism
  • Receptor, Serotonin, 5-HT2C / genetics
  • Receptor, Serotonin, 5-HT2C / metabolism*
  • Transfection
  • Type C Phospholipases / metabolism


  • Diglycerides
  • Ligands
  • Phosphatidylinositols
  • Receptor, Serotonin, 5-HT1B
  • Receptor, Serotonin, 5-HT2C
  • Phosphatidylinositol 3-Kinases
  • Protein-Tyrosine Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Phospholipases A
  • Type C Phospholipases
  • Phospholipase D