title: Ret-dependent and Ret-independent mechanisms of Gfl-induced sensitization.
abstract: 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.
authors: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, 46202, USA. bschmutz@iupui.edu
authors: Brian S
authors: BS
authors: Schmutzler
authors: Shannon
authors: S
authors: Roy
authors: Sherry K
authors: SK
authors: Pittman
authors: Rena M
authors: RM
authors: Meadows
authors: Cynthia M
authors: CM
authors: Hingtgen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015740:Calcitonin Gene-Related Peptide; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D051098:Glial Cell Line-Derived Neurotrophic Factors / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: D051098:Glial Cell Line-Derived Neurotrophic Factors; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse; D015740:Calcitonin Gene-Related Peptide