A heteromeric Texas coral snake toxin targets acid-sensing ion channels to produce pain


Natural products that elicit discomfort or pain represent invaluable tools for probing molecular mechanisms underlying pain sensation1. 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 sensations2,3,4,5,6. As such, venoms provide a rich and varied source of small molecule and protein pharmacophores7,8 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 pain9, 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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Heteromeric toxin from Texas coral snake activates somatosensory neurons.
Figure 2: MitTx activates ASICs.
Figure 3: ASICs are the neuronal receptor for MitTx.
Figure 4: MitTx elicits pain behaviour through ASIC1- and TRPV1-expressing nociceptors.

Accession codes

Data deposits

MitTx-α, MitTx-μ and MttPLA2 cDNA sequences are deposited in GenBank under accession numbers JN613325, JN613326 and JN613327, respectively.


  1. 1

    Basbaum, A. I., Bautista, D. M., Scherrer, G. & Julius, D. Cellular and molecular mechanisms of pain. Cell 139, 267–284 (2009)

  2. 2

    Mebs, D. Venomous and Poisonous Animals: A Handbook for Biologists, and Toxicologists and Toxinologists, Physicians and Pharmacists (CRC Press, 2002)

  3. 3

    Chahl, L. A. & Kirk, E. J. Toxins which produce pain. Pain 1, 3–49 (1975)

  4. 4

    Schmidt, J. O. Biochemistry of insect venoms. Annu. Rev. Entomol. 27, 339–368 (1982)

  5. 5

    Siemens, J. et al. Spider toxins activate the capsaicin receptor to produce inflammatory pain. Nature 444, 208–212 (2006)

  6. 6

    Bohlen, C. J. et al. A bivalent tarantula toxin activates the capsaicin receptor, TRPV1, by targeting the outer pore domain. Cell 141, 834–845 (2010)

  7. 7

    Terlau, H. & Olivera, B. M. Conus venoms: a rich source of novel ion channel-targeted peptides. Physiol. Rev. 84, 41–68 (2004)

  8. 8

    Fry, B. G. et al. The toxicogenomic multiverse: convergent recruitment of proteins into animal venoms. Annu. Rev. Genomics Hum. Genet. 10, 483–511 (2009)

  9. 9

    Morgan, D. L., Borys, D. J., Stanford, R., Kjar, D. & Tobleman, W. Texas coral snake (Micrurus tener) bites. South. Med. J. 100, 152–156 (2007)

  10. 10

    Doley, R. & Kini, R. M. Protein complexes in snake venom. Cell. Mol. Life Sci. 66, 2851–2871 (2009)

  11. 11

    Berg, O. G., Gelb, M. H., Tsai, M. D. & Jain, M. K. Interfacial enzymology: the secreted phospholipase A(2)-paradigm. Chem. Rev. 101, 2613–2654 (2001)

  12. 12

    Waldmann, R., Champigny, G., Bassilana, F., Heurteaux, C. & Lazdunski, M. A proton-gated cation channel involved in acid-sensing. Nature 386, 173–177 (1997)

  13. 13

    Waldmann, R. et al. Molecular cloning of a non-inactivating proton-gated Na+ channel specific for sensory neurons. J. Biol. Chem. 272, 20975–20978 (1997)

  14. 14

    Wu, L. J. et al. Characterization of acid-sensing ion channels in dorsal horn neurons of rat spinal cord. J. Biol. Chem. 279, 43716–43724 (2004)

  15. 15

    Escoubas, P. et al. Isolation of a tarantula toxin specific for a class of proton-gated Na+ channels. J. Biol. Chem. 275, 25116–25121 (2000)

  16. 16

    Chen, X., Kalbacher, H. & Grunder, S. Interaction of acid-sensing ion channel (ASIC) 1 with the tarantula toxin psalmotoxin 1 is state dependent. J. Gen. Physiol. 127, 267–276 (2006)

  17. 17

    Leffler, A., Monter, B. & Koltzenburg, M. The role of the capsaicin receptor TRPV1 and acid-sensing ion channels (ASICS) in proton sensitivity of subpopulations of primary nociceptive neurons in rats and mice. Neuroscience 139, 699–709 (2006)

  18. 18

    Poirot, O., Berta, T., Decosterd, I. & Kellenberger, S. Distinct ASIC currents are expressed in rat putative nociceptors and are modulated by nerve injury. J. Physiol. (Lond.) 576, 215–234 (2006)

  19. 19

    Price, M. P. et al. The DRASIC cation channel contributes to the detection of cutaneous touch and acid stimuli in mice. Neuron 32, 1071–1083 (2001)

  20. 20

    Wemmie, J. A. et al. The acid-activated ion channel ASIC contributes to synaptic plasticity, learning, and memory. Neuron 34, 463–477 (2002)

  21. 21

    Cavanaugh, D. J. et al. Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli. Proc. Natl Acad. Sci. USA 106, 9075–9080 (2009)

  22. 22

    Nishioka, S. A., Silveira, P. V. & Menzes, L. B. Coral snake bite and severe local pain. Ann. Trop. Med. Parasitol. 87, 429–431 (1993)

  23. 23

    Sutherland, S. P., Benson, C. J., Adelman, J. P. & McCleskey, E. W. Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons. Proc. Natl Acad. Sci. USA 98, 711–716 (2001)

  24. 24

    Wemmie, J. A., Price, M. P. & Welsh, M. J. Acid-sensing ion channels: advances, questions and therapeutic opportunities. Trends Neurosci. 29, 578–586 (2006)

  25. 25

    Deval, E. et al. Acid-sensing ion channels (ASICs): pharmacology and implication in pain. Pharmacol. Ther. 128, 549–558 (2010)

  26. 26

    Yu, Y. et al. A nonproton ligand sensor in the acid-sensing ion channel. Neuron 68, 61–72 (2010)

  27. 27

    Ziemann, A. E. et al. The amygdala is a chemosensor that detects carbon dioxide and acidosis to elicit fear behavior. Cell 139, 1012–1021 (2009)

  28. 28

    Askwith, C. C. et al. Neuropeptide FF and FMRFamide potentiate acid-evoked currents from sensory neurons and proton-gated DEG/ENaC channels. Neuron 26, 133–141 (2000)

  29. 29

    Jacobson, M. P. et al. A hierarchical approach to all-atom protein loop prediction. Proteins 55, 351–367 (2004)

  30. 30

    Caterina, M. J. et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288, 306–313 (2000)

Download references


We thank M. Price and M. Welsh for providing ASIC1 and ASIC3 knockout mice; Y. Kelly and J. Poblete for technical assistance; C. Williams for assisting with homology models; F. Findeisen, L. Ma and D. Minor for assistance with ITC experiments; R. Nicoll and members of the Julius laboratory for discussion and comments. This work was supported by a Ruth Kirschstein NIH predoctoral fellowship (F31NS065597 to C.B.), an NIH postdoctoral training grant from the UCSF Cardiovascular Research Institute (to A.C.), a postdoctoral fellowship from the Canadian Institutes of Health Research (to R.S.-N.), the Howard Hughes Medical Institute (K.F.M. and A.L.B.), and the NIH (NCRR P41RR001614 to A.L.B., NCRR P40RR018300-09 to E.S. and NINDS R01NS065071 to D.J.).

Author information

C.B. and A.C. initiated the screen, performed experiments and analysed data. R.S.-N. and A.I.B. performed and analysed behavioural experiments and spinal cord histology. K.F.M., A.L.B., S.Z. and D.K. determined partial protein sequences and performed mass spectrometry measurements. E.S. provided snake venom and tissue. C.B., A.C. and D.J. wrote the manuscript with discussion and contribution from all authors. D.J. supervised the project and provided guidance throughout.

Correspondence to David Julius.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-6 with legends. (PDF 975 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bohlen, C., Chesler, A., Sharif-Naeini, R. et al. A heteromeric Texas coral snake toxin targets acid-sensing ion channels to produce pain. Nature 479, 410–414 (2011). https://doi.org/10.1038/nature10607

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.