title: Identification of a cono-RFamide from the venom ofConus textilethat targets ASIC3 and enhances muscle pain.
abstract: Acid-sensing ion channels (ASICs) are proton-gated Na+channels that are expressed throughout the nervous system. ASICs have been implicated in several neuronal disorders, like ischemic stroke, neuronal inflammation, and pathological pain. Several toxins from venomous animals have been identified that target ASICs with high specificity and potency. These toxins are extremely useful in providing protein pharmacophores and to characterize function and structure of ASICs. Marine cone snails contain a high diversity of toxins in their venom such as conotoxins, which are short polypeptides stabilized by disulfide bonds, and conopeptides, which have no or only one disulfide bond. Whereas conotoxins selectively target specific neuronal proteins, mainly ion channels, the targets of conopeptides are less well known. Here, we perform an in vitro screen of venoms from 18 cone snail species to identify toxins targeting ASICs. We identified a small conopeptide of only four amino acids from the venom ofConus textilethat strongly potentiated currents of ASIC3, which has a specific role in the pain pathway. This peptide, RPRFamide, belongs to the subgroup of cono-RFamides. Electrophysiological characterization of isolated dorsal root ganglion (DRG) neurons revealed that RPRFamide increases their excitability. Moreover, injection of the peptide into the gastrocnemius muscle strongly enhanced acid-induced muscle pain in mice that was abolished by genetic inactivation of ASIC3. In summary, we identified a conopeptide that targets the nociceptor-specific ion channel ASIC3.
authors.affiliation: Institute of Physiology, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, 52074 Aachen, Germany.
authors.forename: Catharina
authors.initials: C
authors.lastname: Reimers
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Cheng-Han
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Interfaculty Institute of Biochemistry, University of Tübingen, 72076 Tuebingen, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Kalbacher
authors.affiliation: Institute of Physiology, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, 52074 Aachen, Germany.
authors.forename: Yuemin
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.|Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.|PhD Program in Translational Medicine, Kaohsiung Medical University and Academia Sinica, Taipei 115, Taiwan.
authors.forename: Chih-Hsien
authors.initials: CH
authors.lastname: Hung
authors.affiliation: Institute of Physiology, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, 52074 Aachen, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: Department of Immunology, Institute for Cell Biology, University of Tübingen, 72076 Tuebingen, Germany.
authors.forename: Lea
authors.initials: L
authors.lastname: Prokop
authors.affiliation: Institute of Legal Medicine, Goethe University of Frankfurt, 60596 Frankfurt, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Kauferstein
authors.affiliation: Institute of Legal Medicine, Goethe University of Frankfurt, 60596 Frankfurt, Germany.
authors.forename: Dietrich
authors.initials: D
authors.lastname: Mebs
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.|PhD Program in Translational Medicine, Kaohsiung Medical University and Academia Sinica, Taipei 115, Taiwan.
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Institute of Physiology, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, 52074 Aachen, Germany; sgruender@ukaachen.de.
authors.forename: Stefan
authors.identifier: 0000-0002-7635-9883
authors.initials: S
authors.lastname: Gründer
mesh_terms: D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D000818:Animals; D020916:Conotoxins / Q000737:chemistry* / Q000633:toxicity*; D052078:Conus Snail / Q000737:chemistry*; D005727:Ganglia, Spinal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology; D063806:Myalgia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D014982:Xenopus laevis
chemical_list: C508378:ASIC3 protein, mouse; D062565:Acid Sensing Ion Channels; D020916:Conotoxins; C059360:Conus textile toxin
keywords: ASIC; acid-sensing ion channel; cone snail; pain; venom