title: Potentiation of acid-sensing ion channel activity by peripheral group I metabotropic glutamate receptor signaling.
abstract: Glutamate activates peripheral group I metabotropic glutamate receptors (mGluRs) and contributes to inflammatory pain. However, it is still not clear the mechanisms are involved in group I mGluR-mediated peripheral sensitization. Herein, we report that group I mGluRs signaling sensitizes acid-sensing ion channels (ASICs) in dorsal root ganglion (DRG) neurons and contributes to acidosis-evoked pain. DHPG, a selective group I mGluR agonist, can potentiate the functional activity of ASICs, which mediated the proton-induced events. DHPG concentration-dependently increased proton-gated currents in DRG neurons. It shifted the proton concentration-response curve upwards, with a 47.3±7.0% increase of the maximal current response to proton. Group I mGluRs, especially mGluR5, mediated the potentiation of DHPG via an intracellular cascade. DHPG potentiation of proton-gated currents disappeared after inhibition of intracellular Gq/11 proteins, PLCβ, PKC or PICK1 signaling. Moreover, DHPG enhanced proton-evoked membrane excitability of rat DRG neurons and increased the amplitude of the depolarization and the number of spikes induced by acid stimuli. Finally, peripherally administration of DHPG dose-dependently exacerbated nociceptive responses to intraplantar injection of acetic acid in rats. Potentiation of ASIC activity by group I mGluR signaling in rat DRG neurons revealed a novel peripheral mechanism underlying group I mGluRs involvement in hyperalgesia.
authors.affiliation: Institute of Ion Channels, Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning, Hubei 437100, PR China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Gan
authors.affiliation: Institute of Ion Channels, Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning, Hubei 437100, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Institute of Ion Channels, Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning, Hubei 437100, PR China.
authors.forename: Cuixia
authors.initials: C
authors.lastname: Ren
authors.affiliation: Institute of Ion Channels, Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning, Hubei 437100, PR China.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Qiu
authors.affiliation: Institute of Ion Channels, Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning, Hubei 437100, PR China.
authors.forename: Yan-Kun
authors.initials: YK
authors.lastname: Li
authors.affiliation: Institute of Ion Channels, Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning, Hubei 437100, PR China. Electronic address: wangping_hu@163.com.
authors.forename: Wang-Ping
authors.initials: WP
authors.lastname: Hu
mesh_terms: D019342:Acetic Acid; D062565:Acid Sensing Ion Channels / Q000502:physiology*; D000138:Acidosis / Q000150:complications / Q000503:physiopathology; D000818:Animals; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology*; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000502:physiology*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D062565:Acid Sensing Ion Channels; D018094:Receptors, Metabotropic Glutamate; D026941:Sodium Channel Blockers; D050916:TRPV Cation Channels; D013779:Tetrodotoxin; D008734:Methoxyhydroxyphenylglycol; C071423:capsazepine; D019342:Acetic Acid; D002211:Capsaicin; C010117:3,4-dihydroxyphenylglycol
keywords: Acid-sensing ion channel; Dorsal root ganglion neuron; Group I metabotropic glutamate receptor; Neuronal excitability; Pain; Proton-gated current