title: Control of Neurotransmission by NaV1.7 in Human, Guinea Pig, and Mouse Airway Parasympathetic Nerves.
abstract: Little is known about the neuronal voltage-gated sodium channels (NaVs) that control neurotransmission in the parasympathetic nervous system. We evaluated the expression of theαsubunits of each of the nine NaVs in human, guinea pig, and mouse airway parasympathetic ganglia. We combined this information with a pharmacological analysis of selective NaV blockers on parasympathetic contractions of isolated airway smooth muscle. As would be expected from previous studies, tetrodotoxin potently blocked the parasympathetic responses in the airways of each species. Gene expression analysis showed that that NaV 1.7 was virtually the only tetrodotoxin-sensitive NaV1 gene expressed in guinea pig and human airway parasympathetic ganglia, where mouse ganglia expressed NaV1.1, 1.3, and 1.7. Using selective pharmacological blockers supported the gene expression results, showing that blocking NaV1.7 alone can abolish the responses in guinea pig and human bronchi, but not in mouse airways. To block the responses in mouse airways requires that NaV1.7 along with NaV1.1 and/or NaV1.3 is blocked. These results may suggest novel indications for NaV1.7-blocking drugs, in which there is an overactive parasympathetic drive, such as in asthma. The data also raise the potential concern of antiparasympathetic side effects for systemic NaV1.7 blockers.
authors.affiliation: The Johns Hopkins University School of Medicine, Division of Allergy and Clinical Immunology, Baltimore, Maryland 21224 (M.Koc., M.Kol., B.J.C., F.R., R.A.H., S.M., B.J.U.); Biomedical Center Martin, Pharmacology and Pathophysiology, Jessenius Faculty of Medicine, Comenius University, Martin 03601, Slovakia (M.Koc., M.Kol.); Almirall S.A., R&D Research Center, Barcelona 08980, Spain (S.F., M.A., M.M.); and Lilly Research Laboratories, Indianapolis, Indiana 46285 (X.C., B.L., B.W., J.M., E.N., J.L.K.).
authors.forename: Michaela
authors.initials: M
authors.lastname: Kocmalova
authors.affiliation: The Johns Hopkins University School of Medicine, Division of Allergy and Clinical Immunology, Baltimore, Maryland 21224 (M.Koc., M.Kol., B.J.C., F.R., R.A.H., S.M., B.J.U.); Biomedical Center Martin, Pharmacology and Pathophysiology, Jessenius Faculty of Medicine, Comenius University, Martin 03601, Slovakia (M.Koc., M.Kol.); Almirall S.A., R&D Research Center, Barcelona 08980, Spain (S.F., M.A., M.M.); and Lilly Research Laboratories, Indianapolis, Indiana 46285 (X.C., B.L., B.W., J.M., E.N., J.L.K.).
authors.forename: Marian
authors.initials: M
authors.lastname: Kollarik
authors.affiliation: The Johns Hopkins University School of Medicine, Division of Allergy and Clinical Immunology, Baltimore, Maryland 21224 (M.Koc., M.Kol., B.J.C., F.R., R.A.H., S.M., B.J.U.); Biomedical Center Martin, Pharmacology and Pathophysiology, Jessenius Faculty of Medicine, Comenius University, Martin 03601, Slovakia (M.Koc., M.Kol.); Almirall S.A., R&D Research Center, Barcelona 08980, Spain (S.F., M.A., M.M.); and Lilly Research Laboratories, Indianapolis, Indiana 46285 (X.C., B.L., B.W., J.M., E.N., J.L.K.).
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Canning
authors.affiliation: The Johns Hopkins University School of Medicine, Division of Allergy and Clinical Immunology, Baltimore, Maryland 21224 (M.Koc., M.Kol., B.J.C., F.R., R.A.H., S.M., B.J.U.); Biomedical Center Martin, Pharmacology and Pathophysiology, Jessenius Faculty of Medicine, Comenius University, Martin 03601, Slovakia (M.Koc., M.Kol.); Almirall S.A., R&D Research Center, Barcelona 08980, Spain (S.F., M.A., M.M.); and Lilly Research Laboratories, Indianapolis, Indiana 46285 (X.C., B.L., B.W., J.M., E.N., J.L.K.).
authors.forename: Fei
authors.initials: F
authors.lastname: Ru
authors.affiliation: The Johns Hopkins University School of Medicine, Division of Allergy and Clinical Immunology, Baltimore, Maryland 21224 (M.Koc., M.Kol., B.J.C., F.R., R.A.H., S.M., B.J.U.); Biomedical Center Martin, Pharmacology and Pathophysiology, Jessenius Faculty of Medicine, Comenius University, Martin 03601, Slovakia (M.Koc., M.Kol.); Almirall S.A., R&D Research Center, Barcelona 08980, Spain (S.F., M.A., M.M.); and Lilly Research Laboratories, Indianapolis, Indiana 46285 (X.C., B.L., B.W., J.M., E.N., J.L.K.).
authors.forename: R
authors.initials: R
authors.lastname: Adam Herbstsomer
authors.affiliation: The Johns Hopkins University School of Medicine, Division of Allergy and Clinical Immunology, Baltimore, Maryland 21224 (M.Koc., M.Kol., B.J.C., F.R., R.A.H., S.M., B.J.U.); Biomedical Center Martin, Pharmacology and Pathophysiology, Jessenius Faculty of Medicine, Comenius University, Martin 03601, Slovakia (M.Koc., M.Kol.); Almirall S.A., R&D Research Center, Barcelona 08980, Spain (S.F., M.A., M.M.); and Lilly Research Laboratories, Indianapolis, Indiana 46285 (X.C., B.L., B.W., J.M., E.N., J.L.K.).
authors.forename: Sonya
authors.initials: S
authors.lastname: Meeker
authors.affiliation: The Johns Hopkins University School of Medicine, Division of Allergy and Clinical Immunology, Baltimore, Maryland 21224 (M.Koc., M.Kol., B.J.C., F.R., R.A.H., S.M., B.J.U.); Biomedical Center Martin, Pharmacology and Pathophysiology, Jessenius Faculty of Medicine, Comenius University, Martin 03601, Slovakia (M.Koc., M.Kol.); Almirall S.A., R&D Research Center, Barcelona 08980, Spain (S.F., M.A., M.M.); and Lilly Research Laboratories, Indianapolis, Indiana 46285 (X.C., B.L., B.W., J.M., E.N., J.L.K.).
authors.forename: Silvia
authors.initials: S
authors.lastname: Fonquerna
authors.affiliation: The Johns Hopkins University School of Medicine, Division of Allergy and Clinical Immunology, Baltimore, Maryland 21224 (M.Koc., M.Kol., B.J.C., F.R., R.A.H., S.M., B.J.U.); Biomedical Center Martin, Pharmacology and Pathophysiology, Jessenius Faculty of Medicine, Comenius University, Martin 03601, Slovakia (M.Koc., M.Kol.); Almirall S.A., R&D Research Center, Barcelona 08980, Spain (S.F., M.A., M.M.); and Lilly Research Laboratories, Indianapolis, Indiana 46285 (X.C., B.L., B.W., J.M., E.N., J.L.K.).
authors.forename: Monica
authors.initials: M
authors.lastname: Aparici
authors.affiliation: The Johns Hopkins University School of Medicine, Division of Allergy and Clinical Immunology, Baltimore, Maryland 21224 (M.Koc., M.Kol., B.J.C., F.R., R.A.H., S.M., B.J.U.); Biomedical Center Martin, Pharmacology and Pathophysiology, Jessenius Faculty of Medicine, Comenius University, Martin 03601, Slovakia (M.Koc., M.Kol.); Almirall S.A., R&D Research Center, Barcelona 08980, Spain (S.F., M.A., M.M.); and Lilly Research Laboratories, Indianapolis, Indiana 46285 (X.C., B.L., B.W., J.M., E.N., J.L.K.).
authors.forename: Montserrat
authors.initials: M
authors.lastname: Miralpeix
authors.affiliation: The Johns Hopkins University School of Medicine, Division of Allergy and Clinical Immunology, Baltimore, Maryland 21224 (M.Koc., M.Kol., B.J.C., F.R., R.A.H., S.M., B.J.U.); Biomedical Center Martin, Pharmacology and Pathophysiology, Jessenius Faculty of Medicine, Comenius University, Martin 03601, Slovakia (M.Koc., M.Kol.); Almirall S.A., R&D Research Center, Barcelona 08980, Spain (S.F., M.A., M.M.); and Lilly Research Laboratories, Indianapolis, Indiana 46285 (X.C., B.L., B.W., J.M., E.N., J.L.K.).
authors.forename: Xian Xuan
authors.initials: XX
authors.lastname: Chi
authors.affiliation: The Johns Hopkins University School of Medicine, Division of Allergy and Clinical Immunology, Baltimore, Maryland 21224 (M.Koc., M.Kol., B.J.C., F.R., R.A.H., S.M., B.J.U.); Biomedical Center Martin, Pharmacology and Pathophysiology, Jessenius Faculty of Medicine, Comenius University, Martin 03601, Slovakia (M.Koc., M.Kol.); Almirall S.A., R&D Research Center, Barcelona 08980, Spain (S.F., M.A., M.M.); and Lilly Research Laboratories, Indianapolis, Indiana 46285 (X.C., B.L., B.W., J.M., E.N., J.L.K.).
authors.forename: Baolin
authors.initials: B
authors.lastname: Li
authors.affiliation: The Johns Hopkins University School of Medicine, Division of Allergy and Clinical Immunology, Baltimore, Maryland 21224 (M.Koc., M.Kol., B.J.C., F.R., R.A.H., S.M., B.J.U.); Biomedical Center Martin, Pharmacology and Pathophysiology, Jessenius Faculty of Medicine, Comenius University, Martin 03601, Slovakia (M.Koc., M.Kol.); Almirall S.A., R&D Research Center, Barcelona 08980, Spain (S.F., M.A., M.M.); and Lilly Research Laboratories, Indianapolis, Indiana 46285 (X.C., B.L., B.W., J.M., E.N., J.L.K.).
authors.forename: Ben
authors.initials: B
authors.lastname: Wilenkin
authors.affiliation: The Johns Hopkins University School of Medicine, Division of Allergy and Clinical Immunology, Baltimore, Maryland 21224 (M.Koc., M.Kol., B.J.C., F.R., R.A.H., S.M., B.J.U.); Biomedical Center Martin, Pharmacology and Pathophysiology, Jessenius Faculty of Medicine, Comenius University, Martin 03601, Slovakia (M.Koc., M.Kol.); Almirall S.A., R&D Research Center, Barcelona 08980, Spain (S.F., M.A., M.M.); and Lilly Research Laboratories, Indianapolis, Indiana 46285 (X.C., B.L., B.W., J.M., E.N., J.L.K.).
authors.forename: Jeff
authors.initials: J
authors.lastname: McDermott
authors.affiliation: The Johns Hopkins University School of Medicine, Division of Allergy and Clinical Immunology, Baltimore, Maryland 21224 (M.Koc., M.Kol., B.J.C., F.R., R.A.H., S.M., B.J.U.); Biomedical Center Martin, Pharmacology and Pathophysiology, Jessenius Faculty of Medicine, Comenius University, Martin 03601, Slovakia (M.Koc., M.Kol.); Almirall S.A., R&D Research Center, Barcelona 08980, Spain (S.F., M.A., M.M.); and Lilly Research Laboratories, Indianapolis, Indiana 46285 (X.C., B.L., B.W., J.M., E.N., J.L.K.).
authors.forename: Eric
authors.initials: E
authors.lastname: Nisenbaum
authors.affiliation: The Johns Hopkins University School of Medicine, Division of Allergy and Clinical Immunology, Baltimore, Maryland 21224 (M.Koc., M.Kol., B.J.C., F.R., R.A.H., S.M., B.J.U.); Biomedical Center Martin, Pharmacology and Pathophysiology, Jessenius Faculty of Medicine, Comenius University, Martin 03601, Slovakia (M.Koc., M.Kol.); Almirall S.A., R&D Research Center, Barcelona 08980, Spain (S.F., M.A., M.M.); and Lilly Research Laboratories, Indianapolis, Indiana 46285 (X.C., B.L., B.W., J.M., E.N., J.L.K.).
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Krajewski
authors.affiliation: The Johns Hopkins University School of Medicine, Division of Allergy and Clinical Immunology, Baltimore, Maryland 21224 (M.Koc., M.Kol., B.J.C., F.R., R.A.H., S.M., B.J.U.); Biomedical Center Martin, Pharmacology and Pathophysiology, Jessenius Faculty of Medicine, Comenius University, Martin 03601, Slovakia (M.Koc., M.Kol.); Almirall S.A., R&D Research Center, Barcelona 08980, Spain (S.F., M.A., M.M.); and Lilly Research Laboratories, Indianapolis, Indiana 46285 (X.C., B.L., B.W., J.M., E.N., J.L.K.) bundem@jhmi.edu.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Undem
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005726:Ganglia, Parasympathetic / Q000187:drug effects / Q000502:physiology*; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000502:physiology*; D009924:Organ Culture Techniques; D017777:Parasympathetic Fibers, Postganglionic / Q000187:drug effects / Q000502:physiology*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D026941:Sodium Channel Blockers