Nociceptive tuning by stem cell factor/c-Kit signaling.
The molecular mechanisms regulating the sensitivity of sensory circuits to environmental stimuli are poorly understood. We demonstrate here a central role for stem cell factor (SCF) and its receptor, c-Kit, in tuning the responsiveness of sensory neurons to natural stimuli. Mice lacking SCF/c-Kit signaling displayed profound thermal hypoalgesia, attributable to a marked elevation in the thermal threshold and reduction in spiking rate of heat-sensitive nociceptors. Acute activation of c-Kit by its ligand, SCF, resulted in a reduced thermal threshold and potentiation of heat-activated currents in isolated small-diameter neurons and thermal hyperalgesia in mice. SCF-induced thermal hyperalgesia required the TRP family cation channel TRPV1. Lack of c-Kit signaling during development resulted in hypersensitivity of discrete mechanoreceptive neuronal subtypes. Thus, c-Kit can now be grouped with a small family of receptor tyrosine kinases, including c-Ret and TrkA, that control the transduction properties of sensory neurons.
Milenkovic
Nevena
N
Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13092 Berlin, Germany.
Frahm
Christina
C
Gassmann
Max
M
Griffel
Carola
C
Erdmann
Bettina
B
Birchmeier
Carmen
C
Lewin
Gary R
GR
Garratt
Alistair N
AN
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002452:Cell Count; D004594:Electrophysiology; D005727:Ganglia, Spinal / Q000502:physiology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000503:physiopathology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008465:Mechanoreceptors / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009154:Mutation / Q000502:physiology; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D010147:Pain Measurement / Q000187:drug effects; D018408:Patch-Clamp Techniques; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012867:Skin / Q000187:drug effects / Q000294:innervation; D019089:Stem Cell Factor / Q000502:physiology*; D050916:TRPV Cation Channels / Q000502:physiology
D019089:Stem Cell Factor; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D002211:Capsaicin; D002118:Calcium