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Insulin signaling inhibits the 5-HT2C receptor in choroid plexus via MAP kinase

Joyce H Hurley1, Shengwen Zhang, Leighan S Bye

  • 1Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA. johurley@iupui.edu

BMC Neuroscience
|June 11, 2003
PubMed
Abstract

Insights

Tyrosine kinase pathways, like insulin signaling, can directly inhibit G protein-coupled receptor (GPCR) activity, specifically the 5-HT2C receptor, through mitogen-activated protein (MAP) kinase regulation.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Neuroscience

Background:

  • G protein-coupled receptors (GPCRs) mediate acute cellular responses, while tyrosine kinase receptors influence long-term cellular changes.
  • The interplay between GPCRs and tyrosine kinase-mediated pathways, particularly mitogen-activated protein (MAP) kinases, remains incompletely understood.
  • It is unclear if tyrosine kinase-MAP kinase pathways regulate GPCRs.

Purpose of the Study:

  • To investigate the regulation of GPCRs by tyrosine kinase-MAP kinase pathways.
  • To elucidate the specific mechanisms by which insulin signaling affects GPCR activity.

Main Methods:

  • Utilized choroid plexus cells expressing the 5-HT2C receptor.
  • Employed the mitogen-activated protein kinase kinase (MEK) inhibitor PD 098059.
  • Assessed the effects of insulin, insulin-like growth factor type 1 (IGF-1), and activated MAP kinase on receptor activity.
  • Mutated a putative MAP kinase site on the 5-HT2C receptor.

Main Results:

  • Insulin significantly reduced 5-HT2C receptor activity, an effect blocked by PD 098059.
  • The inhibitory effects of insulin and IGF-1 were dependent on tyrosine kinase, RAS, and MAP kinase signaling.
  • This regulation appeared specific to the 5-HT2C receptor, as another GPCR in the same signaling pathway was unaffected.
  • Activated MAP kinase mimicked insulin's inhibitory effect, and mutating a MAP kinase site abolished insulin's action.

Conclusions:

  • Insulin signaling directly inhibits 5-HT2C receptor activity.
  • MAP kinase plays a direct role in the regulation of specific GPCR function.

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