Mini-reviewPainful toxins acting at TRPV1
Introduction
Toxins may be employed defensively or aggressively. Plants are well known to discourage predation by animals through the defensive use of toxins that may have an unpleasant taste, act as irritants, cause pain or even death. Animals, conversely, are better known for their aggressive use of toxins in venoms for paralyzing and killing prey but there are also many animals, such as bees, that use toxins defensively to ward off predators or competitors, often by inflicting pain. Many painful venom components are neurotoxins that act directly on receptors or enzymes of the peripheral sensory nerves that sense pain. For example, some painful wasp venom peptide toxins are agonists of kinin receptors and the principal painful bee toxin, melittin, is a potent phospholipase A2 activator that also inhibits protein kinase C and several other protein kinases. Venomous animals that use toxins aggressively for predation have an ideal weapon that they may also use defensively, again often inflicting pain. As a mode of action for defensive toxins, inflicting pain appears ideal, but is of no apparent value in predation. Consequently, it is not clear whether the painful effects of predatory venoms are simply beneficial defensive side-effects of toxins used for predation or whether these venoms include specific defensive toxins. Support for the latter alternative comes from the recent identification of peptide “vanillotoxins” (VaTxs) in tarantula venom that specifically activate the noxious heat-sensing receptor TRPV1 (Fig. 1) (Siemens et al., 2006), well known as the target of capsaicin (Fig. 2), the painful vanilloid toxin in “hot” chilli peppers. Thus in a surprising case of convergent evolution, chilli plants and tarantulas have evolved very different toxins that activate the same pain-sensing receptors in mammals.
Further investigation will be required to determine whether there are other painful toxins that target TRPV1, or other TRP family members that also act as pain sensors. There are, however, some preliminary hints that this may be the case. The burning and tingling neurological sensations typically associated with neurotoxic shellfish poisoning and ciguatera fish poisoning are believed to be due to polyether toxins, such as gambierol and brevetoxin, and these toxins have recently been shown to potentiate activation of TRPV1 by capsaicin (Cuypers et al., 2007). Similarly, components of venom from jellyfish and other cnidaria are able to potentiate the action of capsaicin by preventing desensitization of TRPV1 (Cuypers et al., 2006) but show no direct action on TRPV1 in the absence of capsaicin. The precise venom components mediating these effects are also unknown. Precise components of American funnel web venom, agatoxins (Fig. 2), have been shown to block TRPV1 (Kitaguchi and Swartz, 2005) in a manner that is proposed to be analogous to block by arginine-rich peptides (Planells-Cases et al., 2000) but this effect occurs at relatively low potency and is not specific for TRPV1. Such inhibition of TRPV1 would also cause analgesia rather than pain.
The sequence of the tarantula VaTxs (Fig. 3) identifies them as members of the inhibitor cysteine knot (ICK) peptide family (Siemens et al., 2006), with greatest homology to the sub-family of ICK toxins that modulate voltage gating of potassium channels and are most prominent in the venom of tarantulas (Swartz, 2007). The probable close evolutionary link between this sub-family and VaTxs is supported by the finding that, in addition to activating TRPV1, one of the VaTxs (VaTx1) modulates voltage gating of Kv2.1, a member of the Shab family of voltage-gated potassium (Kv) channels (Siemens et al., 2006). In this review, we will present a brief summary of what is known about the biology and molecular mechanisms of TRPV1 function and the action of non-peptide plant toxins such as capsaicin. Finally we will discuss, in a more speculative manner, the possible mechanism of action of VaTxs on TRPV1, drawing heavily on the analogy of the effects of related ICK toxins on voltage gating of distantly related ion channels.
Section snippets
TRPV1 biology
TRPV1 or the capsaicin receptor, first cloned and characterized by Caterina et al. (1997), is a member of the transient receptor potential gene family of non-selective cation channels, which includes a number of thermosensitive ion channels that are involved in pain pathways, such as TRPV4 (Grant et al., 2007), TRPM8 (Bautista et al., 2007; Dhaka et al., 2007; Colburn et al., 2007) and TRPA1(Kwan et al., 2006; Bautista et al., 2007). TRPV1 is expressed in pain-sensing peripheral sensory neurons
TRPV1 protein structure and function
The TRPV1 protein is a tetrameric (Kedei et al., 2001) integral membrane protein, which in the rat comprises 839 residues, with cytoplasmic N- and C-terminal tails flanking six transmembrane regions (termed S1–S6 here) and a putative pore-lining region between the S5 and S6. The overall membrane topology resembles that of the extensively studied voltage-dependent potassium (Kv) channels, and these studies provide a basic conceptual model for understanding the membrane region of TRP channels (
Non-peptide plant toxins that target TRPV1
Capsaicin (Fig. 2) is a pungent compound from chilli peppers, the fruit of Capsicum frutescens and is the classic vanilloid agonist of TRPV1. The early functional identification of rat TRPV1 cDNA based on activation by capsaicin (Caterina et al., 1997) is the reason for the classification of TRPV1 as the first of the vanilloid receptor sub-family of TRP channels, even though no other TRPV family members respond to vanilloid agonists. TRPV1, 2, 3 and 4 share between 37% and 47% amino acid
Non-peptide animal toxin interactions with TRPV1
The venom of the American funnel web spider Agelenopsis aperta includes high concentrations of two acylpolyamine toxins, agatoxin 489 (Fig. 2) and agatoxin 505, that are known to paralyze insects by inhibiting synaptic glutamate receptors (Adams, 2004; Adams et al., 1989; Skinner et al., 1989) but have recently been shown to also inhibit TRPV1 (Kitaguchi and Swartz, 2005). Based on both the voltage dependence of inhibition and the effect on toxin sensitivity of mutations of channel-lining
Vanillotoxins; ICK peptides that activate TRPV1
The recently identified peptide VaTxs, from tarantula venom, that activate TRPV1 show significant sequence homology to other toxins in the well-described class of ICK peptide toxins (Siemens et al., 2006). VaTxs show the closest homology to a family of the ICK toxins, including hanatoxin, that inhibit voltage-gated cation channels, notably Kv channels, by modulating voltage sensitivity through interactions with the voltage sensor. Indeed, in addition to activating TRPV1, VaTx1 inhibits Kv2.1 by
Acknowledgments
B.C. is a Sir Randal Heymanson Fellow (Howard Florey Institute and Department of Pharmacology, University of Melbourne). Thanks to Dr. Rachelle Gaudet for providing the coordinates of the Ankyrin repeat domain (2PNN) ahead of their release from the Protein Data Bank.
References (75)
Agatoxins: ion channel specific toxins from the American funnel web spider, Agelenopsis aperta
Toxicon
(2004)- et al.
Polyamines are potent ligands for the capsaicin receptor TRPV1
J. Biol. Chem.
(2006) - et al.
Jellyfish and other cnidarian envenomations cause pain by affecting TRPV1 channels
FEBS Lett.
(2006) - et al.
TRPV1 as a key determinant in ciguatera and neurotoxic shellfish poisoning
Biochem. Biophys. Res. Commun.
(2007) - et al.
TRPM8 is required for cold sensation in mice
Neuron
(2007) - et al.
Molecular determinants of vanilloid sensitivity in TRPV1
J. Biol. Chem.
(2004) - et al.
Potassium channel structures: do they conform?
Curr. Opin. Struct. Biol.
(2004) - et al.
From worm to man: three subfamilies of TRP channels
Trends Neurosci.
(2000) - et al.
Molecular basis for species-specific sensitivity to “hot” chili peppers
Cell
(2002) - et al.
Agonist recognition sites in the cytosolic tails of vanilloid receptor 1
J. Biol. Chem.
(2002)