title: A heteromeric Texas coral snake toxin targets acid-sensing ion channels to produce pain.
abstract: Natural products that elicit discomfort or pain represent invaluable tools for probing molecular mechanisms underlying pain sensation. Plant-derived irritants have predominated in this regard, but animal venoms have also evolved to avert predators by targeting neurons and receptors whose activation produces noxious sensations. As such, venoms provide a rich and varied source of small molecule and protein pharmacophores that can be exploited to characterize and manipulate key components of the pain-signalling pathway. With this in mind, here we perform an unbiased in vitro screen to identify snake venoms capable of activating somatosensory neurons. Venom from the Texas coral snake (Micrurus tener tener), whose bite produces intense and unremitting pain, excites a large cohort of sensory neurons. The purified active species (MitTx) consists of a heteromeric complex between Kunitz- and phospholipase-A2-like proteins that together function as a potent, persistent and selective agonist for acid-sensing ion channels (ASICs), showing equal or greater efficacy compared with acidic pH. MitTx is highly selective for the ASIC1 subtype at neutral pH; under more acidic conditions (pH < 6.5), MitTx massively potentiates (>100-fold) proton-evoked activation of ASIC2a channels. These observations raise the possibility that ASIC channels function as coincidence detectors for extracellular protons and other, as yet unidentified, endogenous factors. Purified MitTx elicits robust pain-related behaviour in mice by activation of ASIC1 channels on capsaicin-sensitive nerve fibres. These findings reveal a mechanism whereby snake venoms produce pain, and highlight an unexpected contribution of ASIC1 channels to nociception.
authors.affiliation: Department of Physiology, University of California, San Francisco, California 94158-2517, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Bohlen
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Chesler
authors.forename: Reza
authors.initials: R
authors.lastname: Sharif-Naeini
authors.forename: Katalin F
authors.initials: KF
authors.lastname: Medzihradszky
authors.forename: Sharleen
authors.initials: S
authors.lastname: Zhou
authors.forename: David
authors.initials: D
authors.lastname: King
authors.forename: Elda E
authors.initials: EE
authors.lastname: Sánchez
authors.forename: Alma L
authors.initials: AL
authors.lastname: Burlingame
authors.forename: Allan I
authors.initials: AI
authors.lastname: Basbaum
authors.forename: David
authors.initials: D
authors.lastname: Julius
mesh_terms: D062565:Acid Sensing Ion Channels; D000595:Amino Acid Sequence; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D004546:Elapid Venoms / Q000737:chemistry* / Q000494:pharmacology*; D017815:Elapidae; D006614:Hindlimb / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D059225:Nociception / Q000187:drug effects / Q000502:physiology; D009865:Oocytes; D010146:Pain / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D011522:Protons; D051381:Rats; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D062687:Sodium Channel Agonists; D015222:Sodium Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: C568266:ASIC1 protein, human; C568267:ASIC1 protein, mouse; D062565:Acid Sensing Ion Channels; C568268:Asic1 protein, rat; D004546:Elapid Venoms; D009419:Nerve Tissue Proteins; D011522:Protons; D062687:Sodium Channel Agonists; D015222:Sodium Channels; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D002211:Capsaicin
references.citation: Chem Rev. 2001 Sep;101(9):2613-54
references.pmid: 11749391
references.citation: Annu Rev Genomics Hum Genet. 2009;10:483-511
references.pmid: 19640225
references.citation: Nature. 2006 Nov 9;444(7116):208-12
references.pmid: 17093448
references.citation: Neuroscience. 2006 May 12;139(2):699-709
references.pmid: 16515841
references.citation: Cell. 2009 Oct 16;139(2):267-84
references.pmid: 19837031
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):711-6
references.pmid: 11120882
references.citation: Neuron. 2010 Oct 6;68(1):61-72
references.pmid: 20920791
references.citation: South Med J. 2007 Feb;100(2):152-6
references.pmid: 17330685
references.citation: Neuron. 2001 Dec 20;32(6):1071-83
references.pmid: 11754838
references.citation: Neuron. 2000 Apr;26(1):133-41
references.pmid: 10798398
references.citation: Cell. 2009 Nov 25;139(5):1012-21
references.pmid: 19945383
references.citation: Pharmacol Ther. 2010 Dec;128(3):549-58
references.pmid: 20807551
references.citation: J Gen Physiol. 2006 Mar;127(3):267-76
references.pmid: 16505147
references.citation: Nature. 1997 Mar 13;386(6621):173-7
references.pmid: 9062189
references.citation: Pain. 1975 Mar;1(1):3-49
references.pmid: 800636
references.citation: Trends Neurosci. 2006 Oct;29(10):578-86
references.pmid: 16891000
references.citation: J Biol Chem. 2000 Aug 18;275(33):25116-21
references.pmid: 10829030
references.citation: J Biol Chem. 2004 Oct 15;279(42):43716-24
references.pmid: 15302881
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 2;106(22):9075-80
references.pmid: 19451647
references.citation: Cell Mol Life Sci. 2009 Sep;66(17):2851-71
references.pmid: 19495561
references.citation: Physiol Rev. 2004 Jan;84(1):41-68
references.pmid: 14715910
references.citation: J Physiol. 2006 Oct 1;576(Pt 1):215-34
references.pmid: 16840516
references.citation: Annu Rev Entomol. 1982;27:339-68
references.pmid: 7044266
references.citation: Neuron. 2002 Apr 25;34(3):463-77
references.pmid: 11988176
references.citation: Science. 2000 Apr 14;288(5464):306-13
references.pmid: 10764638
references.citation: Ann Trop Med Parasitol. 1993 Aug;87(4):429-31
references.pmid: 8250638
references.citation: Cell. 2010 May 28;141(5):834-45
references.pmid: 20510930
references.citation: J Biol Chem. 1997 Aug 22;272(34):20975-8
references.pmid: 9261094
references.citation: Proteins. 2004 May 1;55(2):351-67
references.pmid: 15048827