title: Activation of acid-sensing ion channels by localized proton transient reveals their role in proton signaling.
abstract: Extracellular transients of pH alterations likely mediate signal transduction in the nervous system. Neuronal acid-sensing ion channels (ASICs) act as sensors for extracellular protons, but the mechanism underlying ASIC activation remains largely unknown. Here, we show that, following activation of a light-activated proton pump, Archaerhodopsin-3 (Arch), proton transients induced ASIC currents in both neurons and HEK293T cells co-expressing ASIC1a channels. Using chimera proteins that bridge Arch and ASIC1a by a glycine/serine linker, we found that successful coupling occurred within 15 nm distance. Furthermore, two-cell sniffer patch recording revealed that regulated release of protons through either Arch or voltage-gated proton channel Hv1 activated neighbouring cells expressing ASIC1a channels. Finally, computational modelling predicted the peak proton concentration at the intercellular interface to be at pH 6.7, which is acidic enough to activate ASICs in vivo. Our results highlight the pathophysiological role of proton signalling in the nervous system.
authors.affiliation: Discipline of Neuroscience, Department of Anatomy, Histology and Embryology, Collaborative Innovation Center for Brain Science, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Wei-Zheng
authors.initials: WZ
authors.lastname: Zeng
authors.affiliation: Discipline of Neuroscience, Department of Anatomy, Histology and Embryology, Collaborative Innovation Center for Brain Science, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Di-Shi
authors.initials: DS
authors.lastname: Liu
authors.affiliation: Institute of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.affiliation: Institute of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Liang
authors.initials: L
authors.lastname: She
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Long-Jun
authors.initials: LJ
authors.lastname: Wu
authors.affiliation: Discipline of Neuroscience, Department of Anatomy, Histology and Embryology, Collaborative Innovation Center for Brain Science, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Tian-Le
authors.initials: TL
authors.lastname: Xu
mesh_terms: D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D055724:Electrophysiological Phenomena / Q000528:radiation effects; D006801:Humans; D008027:Light; D051379:Mice; D011522:Protons; D015398:Signal Transduction
chemical_list: D062565:Acid Sensing Ion Channels; D011522:Protons