Abstract
A novel L-glutamate-gated anion channel (IscaGluCl1) has been cloned from the black-legged tick, Ixodes scapularis, which transmits multiple pathogens including the agents of Lyme disease and human granulocytic anaplasmosis. When mRNA encoding IscaGluCl1 was expressed in Xenopus laevis oocytes, we detected robust 50–400 nA currents in response to 100 μM L-glutamate. Responses to L-glutamate were concentration-dependent (pEC50 3.64 ± 0.11). Ibotenate was a partial agonist on IscaGluCl1. We detected no response to 100 μM aspartate, quisqualate, kainate, AMPA or NMDA. Ivermectin at 1 μM activated IscaGluCl1, whereas picrotoxinin (pIC50 6.20 ± 0.04) and the phenylpyrazole fipronil (pIC50 6.90 ± 0.04) showed concentration-dependent block of the L-glutamate response. The indole alkaloid okaramine B, isolated from fermentation products of Penicillium simplicissimum (strain AK40) grown on okara pulp, activated IscaGluCl1 in a concentration-dependent manner (pEC50 5.43 ± 0.43) and may serve as a candidate lead compound for the development of new acaricides.
Highlights
Ticks are major ectoparasites of livestock and are vectors of human and animal diseases worldwide (Jongejan and Uilenberg, 2004)
The full-length IscaGluCl1 DNA (1350 nucleotides) encodes a 449 amino acid protein which shows the characteristic features of a Cysloop LGIC subunit including: a large extracellular N-terminal domain, a dicysteine loop (Cys-loop) with cysteines separated by 13 residues, 4 transmembrane (TM) regions and a large intracellular TM3-TM4 loop (Fig. 1)
Orthologues of L-glutamate-gated chloride channels (GluCls) are present in all species of ticks studied to date
Summary
Ticks are major ectoparasites of livestock and are vectors of human and animal diseases worldwide (Jongejan and Uilenberg, 2004). They transmit a greater diversity of infectious agents than any other group of blood-feeding arthropods (Gulia-Nuss et al, 2016), including the Lyme disease spirochaete, Borrelia burgdorferi (Burgdorfer, 1984), and many other human and animal pathogens. Improved understanding of the molecular targets of tick control chemicals (acaricides) will enhance our ability to tackle tick-borne livestock diseases, with important implications for veterinary medicine. GluCls are activated by the endectocide ivermectin (22, 23-dihydro-avermectin B1a), a macrocyclic lactone isolated from the actinomycete, Streptomyces avermitilis, which controls both nematode endoparasites and ectoparasites such as ticks (Rugg et al, 2005). First introduced in 1981, by the second half of that decade ivermectin had become the world's biggest-selling animal health product (Omura and Crump, 2014)
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