Integration of G protein signals by extracellular signal-regulated protein kinases in SK-N-MC neuroepithelioma cells

J Neurochem. 2005 Sep;94(5):1457-70. doi: 10.1111/j.1471-4159.2005.03304.x. Epub 2005 Jun 30.


Mammalian cells often receive multiple extracellular stimuli under physiological conditions, and the various signaling inputs have to be integrated for the processing of complex biological responses. G protein-coupled receptors (GPCRs) are critical players in converting extracellular stimuli into intracellular signals. In this report, we examined the integration of different GPCR signals by mitogen-activated protein kinases (MAPKs) using the SK-N-MC human brain neuroepithelioma cells as a neuronal model. Stimulation of the Gi-coupled neuropeptide Y1 and Gq-coupled muscarinic M1 acetylcholine receptors, but not the Gs-coupled dopamine D1 receptor, led to the activation of extracellular signal-regulated kinase (ERK). All three receptors were also capable of stimulating c-Jun NH2-terminal kinases (JNK) and p38 MAPK. The Gi-mediated ERK activation was completely suppressed upon inhibition of Src tyrosine kinases by PP1, while the Gq-induced response was suppressed by both PP1 and the Ca2+ chelator, BAPTA-AM. In contrast, activations of JNK and p38 by Gs-, Gi-, and Gq-coupled receptors were sensitive to PP1 and BAPTA-AM pretreatments. Simultaneous stimulation of Gi- and Gq-coupled receptors resulted in the synergistic activation of ERK, but not JNK or p38 MAPK. The Gi/Gq-induced synergistic ERK activation was PTX-sensitive, and appeared to be a co-operative effect between Ca2+ and Src family tyrosine kinases. Enhanced ERK activation was associated with an increase in CREB phosphorylation, while the JNK and p38-responsive transcription factor ATF-2 was weakly enhanced upon Gi/Gq-induction. This report provides evidence that G protein signals can be integrated at the level of MAPK, resulting in differential effects on ERK, JNK and p38 MAPK in SK-N-MC cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclases / metabolism
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Calcium Signaling
  • Carbachol / pharmacology
  • Cyclic AMP Response Element-Binding Protein
  • Drug Combinations
  • Drug Synergism
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • GTP-Binding Proteins / metabolism*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Kinase 1 / metabolism
  • MAP Kinase Kinase 2 / metabolism
  • Neuroectodermal Tumors, Primitive, Peripheral / metabolism
  • Neuroectodermal Tumors, Primitive, Peripheral / pathology
  • Neurons / metabolism*
  • Neuropeptide Y / pharmacology
  • Receptor, Muscarinic M1 / metabolism
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Neuropeptide Y / metabolism
  • Signal Transduction*
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured
  • Type C Phospholipases / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism
  • src-Family Kinases / metabolism


  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Drug Combinations
  • Neuropeptide Y
  • Receptor, Muscarinic M1
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide Y
  • Transcription Factors
  • neuropeptide Y-Y1 receptor
  • Carbachol
  • MAP2K2 protein, human
  • src-Family Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP2K1 protein, human
  • Type C Phospholipases
  • GTP-Binding Proteins
  • Adenylyl Cyclases