TRP channels as potential targets for antischistosomals

Abstract

Ion channels are membrane protein complexes that underlie electrical excitability in cells, allowing ions to diffuse through cell membranes in a regulated fashion. They are essential for normal functioning of the neuromusculature and other tissues. Ion channels are also validated targets for many current anthelmintics, yet the properties of only a small subset of ion channels in parasitic helminths have been explored in any detail. Transient receptor potential (TRP) channels comprise a widely diverse superfamily of ion channels with important roles in sensory signaling, regulation of ion homeostasis, organellar trafficking, and other functions. There are several subtypes of TRP channels, including TRPA1 and TRPV1 channels, both of which are involved in, among other functions, sensory, nociceptive, and inflammatory signaling in mammals. Several lines of evidence indicate that TRPA1-like channels in schistosomes exhibit pharmacological sensitivities that differ from their mammalian counterparts and that may signify unique physiological properties as well. Thus, in addition to responding to TRPA1 modulators, schistosome TRPA1-like channels also respond to compounds that in other organisms modulate TRPV1 channels. Notably, TRPV channel genes are not found in schistosome genomes. Here, we review the evidence leading to these conclusions and examine potential implications. We also discuss recent results showing that praziquantel, the current drug of choice against schistosomiasis, selectively targets host TRP channels in addition to its likely primary targets in the parasite. The results we discuss add weight to the notion that schistosome TRP channels are worthy of investigation as candidate therapeutic targets.

Keywords: Capsaicin; Ion channels; Praziquantel; Schistosoma; Schistosomiasis; TRP channels; TRPA1; TRPV1.

Fig. 1

Families of TRP channels. Shown are the 6 mammalian subfamilies of TRP channels. The number of S. mansoni genes for members of each subfamily is indicated in the box. TRPC (Canonical) channels are most closely related to the original Drosophila founding member of the TRP channel superfamily. They are activated by the phospholipase C cascade, among other signals. They may also sense mechanical stretch, and possibly Ca²⁺ store depletion. TRPV (Vanilloid) channels transduce thermal, nociceptive, and inflammatory signals. TRPV1 is the receptor for capsaicin, the primary active ingredient in hot peppers. There are no predicted TRPV channels in schistosomes. TRPA (Ankyrin) channels contain multiple N-terminal ankyrin domains. They are gated by temperature and noxious mechanical stimuli, and like TRPV channels, by nociceptive and inflammatory signals. They are also activated by pungent electrophilic compounds such as allyl isothiocyanate (AITC; found in mustard oil). As in schistosomes, TRPA1 is the sole mammalian TRPA channel. TRPM (Melastatin) channels transduce a variety of sensory signals, including taste and temperature (cold perception). They also respond to osmotic swelling and many chemical compounds. There are several subtypes in mammals, and they represent the most diverse subfamily in schistosomes. TRPP (Polycystin) channels appear to be mechano- or proton sensors. A mutation in one human subtype underlies autosomal dominant polycystic kidney disease (ADPKD), a disorder in which both kidneys show age-dependent massive enlargement. TRPML (Mucolipin) channels are intracellular channels found in endolysosomal vesicles. They play roles in organellar ion homeostasis, autophagy, and nutrient (amino acid) utilization. Mutations in human TRPML1 are the genetic cause of the lysosomal storage disease, mucolipidosis type IV (ML IV), a childhood neurodegenerative disorder. There is one predicted TRPML channel in schistosomes. TRPN and TRPVL subfamilies, absent in both mammals and schistosomes, are not shown (TRPVL is found only in cnidarians and polychaete worms). More details and references can be found in various reviews (Bais and Greenberg, 2016; Nilius and Szallasi, 2014; Peng et al., 2015; Rosasco and Gordon, 2017; Venkatachalam and Montell, 2007).

Fig. 2

Summary of mammalian vs. schistosome TRPA1 pharmacology. Shown is a cartoon representation of the effects of TRPA1 (AITC, 4-HNE) and TRPV1 (capsaicin) activators on mammalian TRPA1 channels (top) and schistosome SmTRPA and ShTRPA channels (bottom), as assayed by heterologous expression and Ca²⁺ imaging (Bais et al., 2018). Capsaicin (Caps, purple) activates mammalian TRPV1 channels but not TRPA1 channels. In contrast, capsaicin activates the schistosome TRPA1-like channels SmTRPA and ShTRPA; there are no TRPV channels in schistosomes (Bais and Greenberg, 2016; Wolstenholme et al., 2011). AITC is a classic TRPA activator (green) that selectively activates mammalian TRPA1 channels. Surprisingly, AITC appears to activate only SmTRPA, and not ShTRPA, a species difference also reflected in dissimilar responses of adult worms to the compound; S. mansoni adults exhibit AITC-induced hyperactivity while S. haematobium adults do not (Bais et al., 2018). In contrast, both SmTRPA and ShTRPA respond to 4-HNE (yellow), a host-derived inflammatory compound that activates TRPA1 channels in other organisms and is associated with nociceptive and inflammatory pathways (Trevisani et al., 2007). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)