Ret-dependent and Ret-independent mechanisms of Gfl-induced sensitization

Mol Pain. 2011 Mar 30;7:22. doi: 10.1186/1744-8069-7-22.


Background: The GDNF family ligands (GFLs) are regulators of neurogenic inflammation and pain. We have previously shown that GFLs increase the release of the sensory neuron neuropeptide, calcitonin gene-related peptide (CGRP) from isolated mouse DRG.

Results: Inhibitors of the mitogen-activated protein kinase (MAPK) pathway abolished the enhancement of CGRP release by GDNF. Neurturin-induced enhancement in the stimulated release of CGRP, used as an indication of sensory neuronal sensitization, was abolished by inhibition of the phosphatidylinositol-3 kinase (PI-3K) pathway. Reduction in Ret expression abolished the GDNF-induced sensitization, but did not fully inhibit the increase in stimulus-evoked release of CGRP caused by neurturin or artemin, indicating the presence of Ret-independent GFL-induced signaling in sensory neurons. Integrin β-1 and NCAM are involved in a component of Ret-independent GFL signaling in sensory neurons.

Conclusions: These data demonstrate the distinct and variable Ret-dependent and Ret-independent signaling mechanisms by which GFLs induce sensitization of sensory neurons. Additionally, there is a clear disconnect between intracellular signaling pathway activation and changes in sensory neuronal function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Calcitonin Gene-Related Peptide
  • Cells, Cultured
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / metabolism
  • Glial Cell Line-Derived Neurotrophic Factors / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Proto-Oncogene Proteins c-ret / genetics
  • Proto-Oncogene Proteins c-ret / metabolism*
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism


  • Glial Cell Line-Derived Neurotrophic Factors
  • Proto-Oncogene Proteins c-ret
  • Ret protein, mouse
  • Calcitonin Gene-Related Peptide