How Nerve Growth Factor Drives Physiological and Inflammatory Expressions of Acid-sensing Ion Channel 3 in Sensory Neurons

Abstract

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. 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. Inflammation is a major source of pain characterized by spontaneity of painful sensations and hypersensitivity. Among proinflammatory mediators, nerve growth factor (NGF) 1The abbreviations used are: NGFnerve growth factorASICacid-sensing ion channelDRGdorsal root gangliaRTreverse transcriptionSEAPsecreted alkaline phosphataseMAPKmitogen-activated protein kinaseMEKMAPK/extracellular signal-regulated kinase kinasePLCphospholipase CPKCprotein kinase CJNKc-Jun N-terminal kinaseHDAChistone deacetylaseTSAtrichostatin AntnucleotideATFactivating transcription factor. is a key signal in inflammatory pain (1.Woolf C.J. Philos. Trans. R. Soc. Lond. B Biol. Sci. 1996; 351: 441-448Crossref PubMed Scopus (186) Google Scholar, 2.Bennett D.L. Neuroscientist. 2001; 7: 13-17Crossref PubMed Scopus (129) Google Scholar, 3.McMahon S.B. Philos. Trans. R. Soc. Lond. B Biol. Sci. 1996; 351: 431-440Crossref PubMed Scopus (284) Google Scholar, 4.Lewin G.R. Mendell L.M. Trends Neurosci. 1993; 16: 353-359Abstract Full Text PDF PubMed Scopus (473) Google Scholar). 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Neurosci. 2001; 21: 8026-8033Crossref PubMed Google Scholar) and for The with a the activity (i.e. the transcriptional was with the activity (i.e. the and the of with protein The level was with the with was with of the and values considered for the of the the expression of genes the regulation the that not to the the signal through the gene We previously that ASIC3 encoding gene could be in functional a to with the a and a activating (8.Mamet J. Baron A. Lazdunski M. Voilley N. J. Neurosci. 2002; 22: 10662-10670Crossref PubMed Google Scholar). 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In the of a transcription factor transcription factor response Inflammation induces expression changes of ion channels, receptors, and in neurons (9.Voilley N. de Weille J. Mamet J. Lazdunski M. J. Neurosci. 2001; 21: 8026-8033Crossref PubMed Google Scholar, S.G. S. Cummins T.R. Black J.A. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: PubMed Scopus Google Scholar, K. S.R. S.B. Akopian A.N. Wood J.N. Neurosci. 1997; PubMed Scopus Google Scholar, K. H. K. M. Brain Res. PubMed Scopus Google Scholar). We have previously that during inflammation current and are increased in neurons and that an increased of neurons current These levels of channel activity neurons to extracellular by producing hyperexcitability, the of hyperalgesia (8.Mamet J. Baron A. Lazdunski M. Voilley N. J. Neurosci. 2002; 22: 10662-10670Crossref PubMed Google Scholar). NGF is a key in inflammatory sensitization of peripheral sensory neurons and is the main proinflammatory factor ASIC3 expression level (8.Mamet J. Baron A. 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