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Curr Biol
2014 Mar 03;245:473-83. doi: 10.1016/j.cub.2014.01.013.
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A tarantula-venom peptide antagonizes the TRPA1 nociceptor ion channel by binding to the S1-S4 gating domain.
Gui J
,
Liu B
,
Cao G
,
Lipchik AM
,
Perez M
,
Dekan Z
,
Mobli M
,
Daly NL
,
Alewood PF
,
Parker LL
,
King GF
,
Zhou Y
,
Jordt SE
,
Nitabach MN
.
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The venoms of predators have been an excellent source of diverse highly specific peptides targeting ion channels. Here we describe the first known peptide antagonist of the nociceptor ion channel transient receptor potential ankyrin 1 (TRPA1). We constructed a recombinant cDNA library encoding ∼100 diverse GPI-anchored peptide toxins (t-toxins) derived from spider venoms and screened this library by coexpression in Xenopus oocytes with TRPA1. This screen resulted in identification of protoxin-I (ProTx-I), a 35-residue peptide from the venom of the Peruvian green-velvet tarantula, Thrixopelma pruriens, as the first known high-affinity peptide TRPA1 antagonist. ProTx-I was previously identified as an antagonist of voltage-gated sodium (NaV) channels. We constructed a t-toxin library of ProTx-I alanine-scanning mutants and screened this library against NaV1.2 and TRPA1. This revealed distinct partially overlapping surfaces of ProTx-I by which it binds to these two ion channels. Importantly, this mutagenesis yielded two novel ProTx-I variants that are only active against either TRPA1or NaV1.2. By testing its activity against chimeric channels, we identified the extracellular loops of the TRPA1 S1-S4 gating domain as the ProTx-I binding site. These studies establish our approach, which we term "toxineering," as a generally applicable method for isolation of novel ion channel modifiers and design of ion channel modifiers with altered specificity. They also suggest that ProTx-I will be a valuable pharmacological reagent for addressing biophysical mechanisms of TRPA1 gating and the physiology of TRPA1 function in nociceptors, as well as for potential clinical application in the context of pain and inflammation.
Andersson,
Clioquinol and pyrithione activate TRPA1 by increasing intracellular Zn2+.
2009, Pubmed
Andersson,
Clioquinol and pyrithione activate TRPA1 by increasing intracellular Zn2+.
2009,
Pubmed
Andersson,
Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress.
2008,
Pubmed
Andrade,
TRPA1 receptor modulation attenuates bladder overactivity induced by spinal cord injury.
2011,
Pubmed
Andrade,
TRPA1 antagonists as potential analgesic drugs.
2012,
Pubmed
Bautista,
TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents.
2006,
Pubmed
Bautista,
Pungent products from garlic activate the sensory ion channel TRPA1.
2005,
Pubmed
Bessac,
TRPA1 is a major oxidant sensor in murine airway sensory neurons.
2008,
Pubmed
Bosmans,
Deconstructing voltage sensor function and pharmacology in sodium channels.
2008,
Pubmed
,
Xenbase
Catterall,
Membrane potential-dependent binding of scorpion toxin to the action potential Na+ ionophore. Studies with a toxin derivative prepared by lactoperoxidase-catalyzed iodination.
1977,
Pubmed
Chen,
Molecular diversity and evolution of cystine knot toxins of the tarantula Chilobrachys jingzhao.
2008,
Pubmed
Chen,
Transcriptome analysis revealed novel possible venom components and cellular processes of the tarantula Chilobrachys jingzhao venom gland.
2008,
Pubmed
Chen,
Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation.
2011,
Pubmed
da Costa,
The involvement of the transient receptor potential A1 (TRPA1) in the maintenance of mechanical and cold hyperalgesia in persistent inflammation.
2010,
Pubmed
Dai,
Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain.
2007,
Pubmed
Du,
Differential expression profile of cold (TRPA1) and cool (TRPM8) receptors in human urogenital organs.
2008,
Pubmed
Dutertre,
Use of venom peptides to probe ion channel structure and function.
2010,
Pubmed
Earley,
Endothelium-dependent cerebral artery dilation mediated by TRPA1 and Ca2+-Activated K+ channels.
2009,
Pubmed
Eid,
HC-030031, a TRPA1 selective antagonist, attenuates inflammatory- and neuropathy-induced mechanical hypersensitivity.
2008,
Pubmed
Escalera,
TRPA1 mediates the noxious effects of natural sesquiterpene deterrents.
2008,
Pubmed
Fletcher,
The structure of a novel insecticidal neurotoxin, omega-atracotoxin-HV1, from the venom of an Australian funnel web spider.
1997,
Pubmed
Gratzke,
Transient receptor potential A1 and cannabinoid receptor activity in human normal and hyperplastic prostate: relation to nerves and interstitial cells.
2010,
Pubmed
Hill,
TRPA1 is differentially modulated by the amphipathic molecules trinitrophenol and chlorpromazine.
2007,
Pubmed
Hinman,
TRP channel activation by reversible covalent modification.
2006,
Pubmed
Ibañez-Tallon,
Tethering naturally occurring peptide toxins for cell-autonomous modulation of ion channels and receptors in vivo.
2004,
Pubmed
,
Xenbase
King,
Venoms as a platform for human drugs: translating toxins into therapeutics.
2011,
Pubmed
Kremeyer,
A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome.
2010,
Pubmed
Macpherson,
Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines.
2007,
Pubmed
Macpherson,
The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin.
2005,
Pubmed
Maggio,
Scanning mutagenesis of a Janus-faced atracotoxin reveals a bipartite surface patch that is essential for neurotoxic function.
2002,
Pubmed
Meseguer,
Transient receptor potential channels in sensory neurons are targets of the antimycotic agent clotrimazole.
2008,
Pubmed
Middleton,
Two tarantula peptides inhibit activation of multiple sodium channels.
2002,
Pubmed
Montell,
The TRP superfamily of cation channels.
2005,
Pubmed
Moran,
Transient receptor potential channels as therapeutic targets.
2011,
Pubmed
Nagata,
Nociceptor and hair cell transducer properties of TRPA1, a channel for pain and hearing.
2005,
Pubmed
Nilius,
TRP channels in disease.
2007,
Pubmed
Obata,
TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury.
2005,
Pubmed
Ohkubo,
Tarantula toxin ProTx-I differentiates between human T-type voltage-gated Ca2+ Channels Cav3.1 and Cav3.2.
2010,
Pubmed
,
Xenbase
Patapoutian,
Transient receptor potential channels: targeting pain at the source.
2009,
Pubmed
Petrus,
A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition.
2007,
Pubmed
,
Xenbase
Phillips,
Voltage-sensor activation with a tarantula toxin as cargo.
2005,
Pubmed
Priest,
ProTx-I and ProTx-II: gating modifiers of voltage-gated sodium channels.
2007,
Pubmed
Ren,
A prokaryotic voltage-gated sodium channel.
2001,
Pubmed
Rogers,
Molecular determinants of high affinity binding of alpha-scorpion toxin and sea anemone toxin in the S3-S4 extracellular loop in domain IV of the Na+ channel alpha subunit.
1996,
Pubmed
Smith,
Molecular interactions of the gating modifier toxin ProTx-II with NaV 1.5: implied existence of a novel toxin binding site coupled to activation.
2007,
Pubmed
Snutch,
Targeting chronic and neuropathic pain: the N-type calcium channel comes of age.
2005,
Pubmed
Sokolov,
Inhibition of sodium channel gating by trapping the domain II voltage sensor with protoxin II.
2008,
Pubmed
,
Xenbase
Story,
ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures.
2003,
Pubmed
Streng,
Distribution and function of the hydrogen sulfide-sensitive TRPA1 ion channel in rat urinary bladder.
2008,
Pubmed
Swartz,
Hanatoxin modifies the gating of a voltage-dependent K+ channel through multiple binding sites.
1997,
Pubmed
,
Xenbase
Swartz,
Mapping the receptor site for hanatoxin, a gating modifier of voltage-dependent K+ channels.
1997,
Pubmed
Tedford,
Scanning mutagenesis of omega-atracotoxin-Hv1a reveals a spatially restricted epitope that confers selective activity against insect calcium channels.
2004,
Pubmed
Trevisani,
4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1.
2007,
Pubmed
Tsetlin,
Polypeptide and peptide toxins, magnifying lenses for binding sites in nicotinic acetylcholine receptors.
2009,
Pubmed
Viana,
TRPA1 modulators in preclinical development.
2009,
Pubmed
Wang,
Molecular surface of tarantula toxins interacting with voltage sensors in K(v) channels.
2004,
Pubmed
,
Xenbase
Wang,
Phospholipase C and protein kinase A mediate bradykinin sensitization of TRPA1: a molecular mechanism of inflammatory pain.
2008,
Pubmed
Wang,
Discovery and characterization of a family of insecticidal neurotoxins with a rare vicinal disulfide bridge.
2000,
Pubmed
Warmke,
Functional expression of Drosophila para sodium channels. Modulation by the membrane protein TipE and toxin pharmacology.
1997,
Pubmed
,
Xenbase
Wu,
Phase coupling of a circadian neuropeptide with rest/activity rhythms detected using a membrane-tethered spider toxin.
2008,
Pubmed
,
Xenbase
Wu,
International Union of Basic and Clinical Pharmacology. LXXVI. Current progress in the mammalian TRP ion channel family.
2010,
Pubmed
Xiao,
Identification of transmembrane domain 5 as a critical molecular determinant of menthol sensitivity in mammalian TRPA1 channels.
2008,
Pubmed
