GFR α2/neurturin signalling regulates noxious heat transduction in isolectin B4‐binding mouse sensory neurons

Abstract

The GFR α2 receptor is the cognate co-receptor for the neurotrophic factor neurturin and GFR α2 is selectively expressed by isolectin B₄ (IB₄)-binding nociceptive sensory neurons. Here, we used two physiological approaches in combination with mice that have a targeted deletion of the GFR α2 gene (GFR α2 −/− mice) in order to determine whether GFR α2/neurturin signalling regulates the functional properties or the survival of IB₄-binding nociceptors. Because 50 % of IB₄-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 IB₄-positive and -negative small-diameter neurons isolated from adult GFR α2 −/− and littermate control mice. The percentage of IB₄-positive neurons that had large (> 100 pA) heat-evoked inward currents was severely reduced in GFR α2 −/− 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 IB₄-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 IB₄-positive C fibres, was normal. Our data are the first to indicate a transduction-function role for GFR α2/neurturin signalling in a specific class of sensory neurons.