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.
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MitTx-α, MitTx-μ and MttPLA2 cDNA sequences are deposited in GenBank under accession numbers JN613325, JN613326 and JN613327, respectively.
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.).
The file contains Supplementary Figures 1-6 with legends.
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Molecular Brain (2016)