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Activation of MAP kinase by MC4-R through PI3 kinase

Aurawan Vongs1, Nicole M Lynn, Charles I Rosenblum

  • 1Department of Metabolic Research-Obesity, Merck Research Laboratories, Merck and Co., P.O. Box 2000, RY80M-213 Rahway, NJ 07065, USA.

Regulatory Peptides
|June 5, 2004
PubMed

Insights

Melanocortin 4 receptor (MC4-R) activation triggers both cAMP and MAPK pathways. This study reveals MC4-R signaling involves phosphatidylinositol 3-kinase (PI3K) in activating p42/p44 MAPK.

Area of Science:

  • Cellular signaling pathways
  • Receptor pharmacology
  • Molecular biology

Background:

  • The melanocortin 4 receptor (MC4-R) is a G protein-coupled receptor primarily involved in regulating energy homeostasis.
  • MC4-R is known to activate adenylyl cyclase, leading to increased cyclic AMP (cAMP) production upon agonist binding.

Purpose of the Study:

  • To investigate the downstream signaling pathways activated by the melanocortin 4 receptor (MC4-R) beyond cAMP production.
  • To determine if mitogen-activated protein kinases (MAPKs) are activated by MC4-R stimulation and to elucidate the signaling cascade involved.

Main Methods:

  • Utilized stably transfected CHO-K1 cells expressing MC4-R.
  • Stimulated cells with the MC4-R agonist NDP-alpha-MSH and observed responses.
  • Employed MC4-R antagonist SHU-9119 to confirm receptor specificity.
  • Used phosphatidylinositol 3-kinase (PI3K) inhibitors (wortmannin, LY294002) and a protein kinase A (PKA) inhibitor (Rp-cAMPS) to dissect the signaling pathway.

Main Results:

  • MC4-R activation by NDP-alpha-MSH led to the activation of p42 (ERK2) and p44 (ERK1) MAPKs in a time- and dose-dependent manner.
  • This MAPK activation was specifically blocked by the MC4-R antagonist SHU-9119.
  • Inhibition of PI3K with wortmannin or LY294002 abolished p42/p44 MAPK activation.
  • Conversely, the PKA inhibitor Rp-cAMPS did not affect MC4-R-mediated MAPK activation.

Conclusions:

  • MC4-R signaling extends to the activation of the p42/p44 MAPK pathway.
  • The activation of the MAPK pathway by MC4-R is dependent on phosphatidylinositol 3-kinase (PI3K) activity.
  • The findings suggest that inositol triphosphate mediates the signal transduction from MC4-R to the MAPK pathway, independent of PKA/cAMP.

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