The fungal alkaloid Okaramine-B activates an L-glutamate-gated chloride channel from Ixodes scapularis, a tick vector of Lyme disease

Furutani, Shogo; Ihara, Makoto; Lees, Kristin; Buckingham, Steven D.; Partridge, Frederick A.; David, Jonathan A.; Patel, Rohit; Warchal, Scott; Mellor, Ian R.; Matsuda, Kazuhiko; Sattelle, David B.

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.

Citation

Furutani, S., Ihara, M., Lees, K., Buckingham, S. D., Partridge, F. A., David, J. A., …Sattelle, D. B. (2018). The fungal alkaloid Okaramine-B activates an L-glutamate-gated chloride channel from Ixodes scapularis, a tick vector of Lyme disease. International Journal for Parasitology: Drugs and Drug Resistance, 8(2), 350-360. https://doi.org/10.1016/j.ijpddr.2018.06.001

• Journal Article Type: Article
• Acceptance Date: Jun 3, 2018
• Online Publication Date: Jun 4, 2018
• Publication Date: Aug 1, 2018
• Deposit Date: Dec 5, 2018
• Publicly Available Date: Dec 6, 2018
• Journal: International Journal for Parasitology: Drugs and Drug Resistance
• Print ISSN: 2211-3207
• Electronic ISSN: 2211-3207
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Issue: 2
• Pages: 350-360
• DOI: https://doi.org/10.1016/j.ijpddr.2018.06.001
• Keywords: Glutamate-gated chloride channel; Tick Ixodes scapularis; Ivermectin; Okaramine B; Acaricide
• Public URL: https://nottingham-repository.worktribe.com/output/1163011
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S2211320717301148?via%3Dihub
• Additional Information: This article is maintained by: Elsevier; Article Title: The fungal alkaloid Okaramine-B activates an L-glutamate-gated chloride channel from Ixodes scapularis, a tick vector of Lyme disease; Journal Title: International Journal for Parasitology: Drugs and Drug Resistance; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.ijpddr.2018.06.001; Content Type: article; Copyright: © 2018 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology.
• Contract Date: Dec 6, 2018