GFR alpha2/neurturin signalling regulates noxious heat transduction in isolectin B4-binding mouse sensory neurons.
The GFR alpha2 receptor is the cognate co-receptor for the neurotrophic factor neurturin and GFR alpha2 is selectively expressed by isolectin B(4) (IB(4))-binding nociceptive sensory neurons. Here, we used two physiological approaches in combination with mice that have a targeted deletion of the GFR alpha2 gene (GFR alpha2 -/- mice) in order to determine whether GFR alpha2/neurturin signalling regulates the functional properties or the survival of IB(4)-binding nociceptors. Because 50 % of IB(4)-binding neurons respond to noxious heat and because patch clamp recordings of isolated dorsal root ganglion sensory neurons allow one to neurochemically identify subpopulations of neurons, we analysed the noxious heat responsiveness of IB(4)-positive and -negative small-diameter neurons isolated from adult GFR alpha2 -/- and littermate control mice. The percentage of IB(4)-positive neurons that had large (> 100 pA) heat-evoked inward currents was severely reduced in GFR alpha2 -/- mice (12 %) compared to wild-type littermates (47 %), and this loss in large-magnitude heat currents was accounted for by an increase in neurons with very small (< 100 pA) heat-evoked currents as well as an increase in neurons with no detectable heat current. Counts of IB(4)-positive and -negative neurons, as well as counts of unmyelinated axons in the saphenous nerve, confirmed that the loss in neurons with large-amplitude heat currents was due to a deficit in heat transduction and not a decrease in cell survival. The effect was modality specific for heat because mechanical transduction of all fibre types, including IB(4)-positive C fibres, was normal. Our data are the first to indicate a transduction-function role for GFR alpha2/neurturin signalling in a specific class of sensory neurons.
Stucky
Cheryl L
CL
Growth Factors and Regeneration Group, Department of Neuroscience, Max Delbrück Center for Molecular Medicine, Robert Rössle Str. 10, Berlin D-13092, Germany.
Rossi
Jari
J
Airaksinen
Matti S
MS
Lewin
Gary R
GR
D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D029721:Drosophila Proteins; D004553:Electric Conductivity; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006023:Glycoproteins; D006358:Hot Temperature; D066298:In Vitro Techniques; D037102:Lectins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000502:physiology*; D009475:Neurons, Afferent / Q000502:physiology*; D051101:Neurturin; D009619:Nociceptors / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D012016:Reference Values; D015398:Signal Transduction / Q000502:physiology*
D029721:Drosophila Proteins; C494991:Gfra2 protein, mouse; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006023:Glycoproteins; D037102:Lectins; D009414:Nerve Growth Factors; D051101:Neurturin; C495056:Nrtn protein, mouse; D011518:Proto-Oncogene Proteins; C473590:isolectin B4-binding glycoprotein, mouse; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila