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Review
. 2012 Sep 1;60(3):254-64.
doi: 10.1016/j.toxicon.2012.04.336. Epub 2012 Apr 14.

Receptor-targeting mechanisms of pain-causing toxins: How ow?

Christopher J Bohlen  1 , David Julius
Affiliations
Review

Receptor-targeting mechanisms of pain-causing toxins: How ow?

Christopher J Bohlen et al. Toxicon. .

Abstract

Venoms often target vital processes to cause paralysis or death, but many types of venom also elicit notoriously intense pain. While these pain-producing effects can result as a byproduct of generalized tissue trauma, there are now multiple examples of venom-derived toxins that target somatosensory nerve terminals in order to activate nociceptive (pain-sensing) neural pathways. Intriguingly, investigation of the venom components that are responsible for evoking pain has revealed novel roles and/or configurations of well-studied toxin motifs. This review serves to highlight pain-producing toxins that target the capsaicin receptor, TRPV1, or members of the acid-sensing ion channel family, and to discuss the utility of venom-derived multivalent and multimeric complexes.

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Figures

Figure 1
Figure 1. Toxins targeting somatosensory receptors
(Left) Two of the four TRPV1 subunits are shown schematically with six gray bars representing transmembrane helices. TRPV1 detects physical and chemical signals from the environment, including acidic pH and hot temperatures. Plant-derived irritants, cnidarian extracts, and toxins from tarantula venom mimic these harmful stimuli by promoting TRPV1 activation. TRPV1 is sensitized by phospoholipase C activation triggered by inflammatory signaling molecules such as bradykinin or ATP that are released downstream from venom lipases, proteases, and kallikreins. Other toxins, such as Bv8 from frog skin, produce TRPV1 sensitization through direct activation of GPCRs. (Right) ASICs are trimeric channels with each subunit containing two transmembrane domains. ASICs are activated by pain-causing toxins from some coral snake venoms as well as acidic pH. Two ASIC-inhibiting toxins have been identified from tarantula and sea anemone, respectively.
Figure 2
Figure 2. Strengthened binding of a bivalent ligand, DkTx, to its receptor, TRPV1
(Left) DkTx activates TRPV1 by binding to the extracellular region near the fifth and sixth transmembrane domains (illustrated as in Figure 1). (Middle) Once one ICK domain (red triangle) has bound to the receptor, the second domain is restricted to a minute volume determined by the length of the toxin's linker region. The high local concentration of the second domain near the binding site of an adjacent subunit results its rapid binding. NA represents Avogadro's number and r represents the length of the linker between ICK domains. (Right) Both ICK domains must dissociate for the channel to remain closed, but when one domain dissociates, it is likely to rapidly bind again before the second domain escapes.
Figure 3
Figure 3. Multimeric venom toxins
A diversity of homo- and hetero-multimeric protein toxins have been identified from venom, either as non-covalent or disulfide-linked complexes. A number of common toxin structural scaffolds (Legend, right) can be recruited to assemble toxin complexes with novel functions.
See this image and copyright information in PMC

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