How nerve growth factor drives physiological and inflammatory expressions of acid-sensing ion channel 3 in sensory neurons.
Nerve growth factor (NGF) is a key element of inflammatory pain. It induces hyperalgesia by up-regulating the transcription of genes encoding receptors, ion channels, and neuropeptides. Acid-sensing ion channel 3 (ASIC3), a depolarizing sodium channel gated by protons during tissue acidosis, is specifically expressed in sensory neurons. It has been associated to cardiac ischemic and inflammatory pains. We previously showed that low endogenous NGF was responsible for ASIC3 basal expression and high NGF during inflammation increased ASIC3 expression parallely to the development of neuron hyperexcitability associated with hyperalgesia. NGF is known to activate numerous signaling pathways through trkA and p75 receptors. We now show that (i). NGF controls ASIC3 basal expression through constitutive activation of a trkA/phospholipase C/protein kinase C pathway, (ii). high inflammatory-like NGF induces ASIC3 overexpression through a trkA/JNK/p38MAPK pathway and a p75-dependent mechanism as a transcriptional switch, and (iii). NGF acts through AP1 response elements in ASIC3 encoding gene promoter. These new data indicate potential targets that could be used to develop new treatments against inflammatory pain.
Mamet
Julien
J
Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, UMR 6097, Sophia Antipolis, 06560 Valbonne, France.
Lazdunski
Michel
M
Voilley
Nicolas
N
D062565:Acid Sensing Ion Channels; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D007249:Inflammation / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009475:Neurons, Afferent / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020917:Receptor, trkA / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism
C568269:ASIC3 protein, rat; D062565:Acid Sensing Ion Channels; D017931:DNA Primers; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D015222:Sodium Channels; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D011493:Protein Kinase C; D010738:Type C Phospholipases