title: Serotonin facilitates peripheral pain sensitivity in a manner that depends on the nonproton ligand sensing domain of ASIC3 channel.
abstract: Tissue acidosis and inflammatory mediators play critical roles in inflammatory pain. Extracellular acidosis activates acid-sensing ion channels (ASICs), which have emerged as key sensors for extracellular protons in the central and peripheral nervous systems and play key roles in pain sensation and transmission. Additionally, inflammatory mediators, such as serotonin (5-HT), are known to enhance pain sensation. However, functional interactions among protons, inflammatory mediators, and ASICs in pain sensation are poorly understood. In the present study, we show that 5-HT, a classical pro-inflammatory mediator, specifically enhances the proton-evoked sustained, but not transient, currents mediated by homomeric ASIC3 channels and heteromeric ASIC3/1a and ASIC3/1b channels. Unexpectedly, the effect of 5-HT on ASIC3 channels does not involve activation of 5-HT receptors, but is mediated via a functional interaction between 5-HT and ASIC3 channels. We further show that the effect of 5-HT on ASIC3 channels depends on the newly identified nonproton ligand sensing domain. Finally, coapplication of 5-HT and acid significantly increased pain-related behaviors as assayed by the paw-licking test in mice, which was largely attenuated in ASIC3 knock-out mice, and inhibited by the nonselective ASIC inhibitor amiloride. Together, these data identify ASIC3 channels as an unexpected molecular target for acute actions of 5-HT in inflammatory pain sensation and reveal an important role of ASIC3 channels in regulating inflammatory pain via coincident detection of extracellular protons and inflammatory mediators.
authors: Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors: Xiang
authors: X
authors: Wang
authors: Wei-Guang
authors: WG
authors: Li
authors: Ye
authors: Y
authors: Yu
authors: Xian
authors: X
authors: Xiao
authors: Jin
authors: J
authors: Cheng
authors: Wei-Zheng
authors: WZ
authors: Zeng
authors: Zhong
authors: Z
authors: Peng
authors: Michael
authors: M
authors: Xi Zhu
authors: Tian-Le
authors: TL
authors: Xu
mesh_terms: D062565:Acid Sensing Ion Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D000704:Analysis of Variance; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009437:Neuralgia / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D017288:Pain Threshold / Q000187:drug effects* / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D017434:Protein Structure, Tertiary; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011522:Protons; D011869:Radioligand Assay; D051381:Rats; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics; D012701:Serotonin / Q000494:pharmacology*; D018490:Serotonin Agents / Q000494:pharmacology; D013116:Spinal Cord / Q000378:metabolism; D014162:Transfection; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: C568269:ASIC3 protein, rat; D062565:Acid Sensing Ion Channels; D008024:Ligands; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D011522:Protons; D044405:Receptor, Serotonin, 5-HT2C; D018490:Serotonin Agents; D014316:Tritium; D012701:Serotonin; D018698:Glutamic Acid; D002118:Calcium