title: Three Peptide Modulators of the Human Voltage-Gated Sodium Channel 1.7, an Important Analgesic Target, from the Venom of an Australian Tarantula.
abstract: Voltage-gated sodium (NaV) channels are responsible for propagating action potentials in excitable cells. NaV1.7 plays a crucial role in the human pain signalling pathway and it is an important therapeutic target for treatment of chronic pain. Numerous spider venom peptides have been shown to modulate the activity of NaV channels and these peptides represent a rich source of research tools and therapeutic lead molecules. The aim of this study was to determine the diversity of NaV1.7-active peptides in the venom of an Australian Phlogius sp. tarantula and to characterise their potency and subtype selectivity. We isolated three novel peptides, μ-TRTX-Phlo1a, -Phlo1b and -Phlo2a, that inhibit human NaV1.7 (hNaV1.7). Phlo1a and Phlo1b are 35-residue peptides that differ by one amino acid and belong in NaSpTx family 2. The partial sequence of Phlo2a revealed extensive similarity with ProTx-II from NaSpTx family 3. Phlo1a and Phlo1b inhibit hNaV1.7 with IC50 values of 459 and 360 nM, respectively, with only minor inhibitory activity on rat NaV1.2 and hNaV1.5. Although similarly potent at hNaV1.7 (IC50 333 nM), Phlo2a was less selective, as it also potently inhibited rNaV1.2 and hNaV1.5. All three peptides cause a depolarising shift in the voltage-dependence of hNaV1.7 activation.
authors.affiliation: The University of Queensland, Institute for Molecular Bioscience, St Lucia, Queensland 4072, Australia. chun.chow@uqconnect.edu.au.
authors.forename: Chun Yuen
authors.initials: CY
authors.lastname: Chow
authors.affiliation: The University of Queensland, Institute for Molecular Bioscience, St Lucia, Queensland 4072, Australia. b.cristoforiarmstrong@uq.edu.au.
authors.forename: Ben
authors.initials: B
authors.lastname: Cristofori-Armstrong
authors.affiliation: The University of Queensland, Institute for Molecular Bioscience, St Lucia, Queensland 4072, Australia. e.undheim@imb.uq.edu.au.
authors.forename: Eivind A B
authors.initials: EA
authors.lastname: Undheim
authors.affiliation: The University of Queensland, Institute for Molecular Bioscience, St Lucia, Queensland 4072, Australia. glenn.king@imb.uq.edu.au.
authors.forename: Glenn F
authors.initials: GF
authors.lastname: King
authors.affiliation: The University of Queensland, Institute for Molecular Bioscience, St Lucia, Queensland 4072, Australia. l.rash@uq.edu.au.
authors.forename: Lachlan D
authors.initials: LD
authors.lastname: Rash
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000595:Amino Acid Sequence; D000700:Analgesics / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001315:Australia; D006801:Humans; D008969:Molecular Sequence Data; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D010446:Peptide Fragments / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013111:Spider Venoms / Q000737:chemistry*; D014162:Transfection; D061567:Voltage-Gated Sodium Channel Blockers / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D014982:Xenopus laevis
chemical_list: D000700:Analgesics; D062556:NAV1.7 Voltage-Gated Sodium Channel; D010446:Peptide Fragments; C486866:SCN9A protein, human; D013111:Spider Venoms; D061567:Voltage-Gated Sodium Channel Blockers
keywords: NaV1.7; Phlogius sp.; ion channel; mass spectrometry; spider venom; two-electrode voltage clamp electrophysiology; venom peptide; voltage-gated sodium channel