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

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

doi:10.1016/j.ijpddr.2018.06.001

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

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

School of Biology

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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.

Original language	English
Pages (from-to)	350-360
Number of pages	11
Journal	International Journal for Parasitology: Drugs and Drug Resistance
Volume	8
Issue number	2
Early online date	4 Jun 2018
DOIs	https://doi.org/10.1016/j.ijpddr.2018.06.001
Publication status	Published - Aug 2018

Keywords

Glutamate-gated-chloride channel
Tick Ixodes scapularis
Ivermectin
Okaramine B
Acaricide

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Furutani_2018_IJPDDR_Okaramine-B_CC
© 2018 Published by Elsevier Ltd on behalf of Australian Society for Parasitology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
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Furutani, S., Ihara, M., Lees, K., Buckingham, S. D., Partridge, F. A., David, J. A., Patel, R., Warchal, S., Mellor, I. R., Matsuda, K., & 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

@article{ddeb8c3ccae34b5c8fba9f965da0a7a1,

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

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.",

keywords = "Glutamate-gated-chloride channel, Tick Ixodes scapularis, Ivermectin, Okaramine B, Acaricide",

author = "Shogo Furutani and Makoto Ihara and Kristin Lees and Buckingham, {Steven D.} and Partridge, {Frederick A.} and David, {Jonathan A.} and Rohit Patel and Scott Warchal and Mellor, {Ian R.} and Kazuhiko Matsuda and Sattelle, {David B.}",

note = "This work was supported by Merial Ltd., The Japan Society for the Promotion of Sciences (KAKENHI, Grant number: 17H01472) and The UK Medical Research Council.",

year = "2018",

month = aug,

doi = "10.1016/j.ijpddr.2018.06.001",

language = "English",

volume = "8",

pages = "350--360",

journal = "International Journal for Parasitology: Drugs and Drug Resistance",

issn = "2211-3207",

publisher = "Elsevier",

number = "2",

}

Furutani, S, Ihara, M, Lees, K, Buckingham, SD, Partridge, FA, David, JA, Patel, R, Warchal, S, Mellor, IR, Matsuda, K & Sattelle, DB 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, vol. 8, no. 2, pp. 350-360. https://doi.org/10.1016/j.ijpddr.2018.06.001

TY - JOUR

T1 - The fungal alkaloid Okaramine-B activates an L-glutamate-gated chloride channel from Ixodes scapularis, a tick vector of Lyme disease

AU - Furutani, Shogo

AU - Ihara, Makoto

AU - Lees, Kristin

AU - Buckingham, Steven D.

AU - Partridge, Frederick A.

AU - David, Jonathan A.

AU - Patel, Rohit

AU - Warchal, Scott

AU - Mellor, Ian R.

AU - Matsuda, Kazuhiko

AU - Sattelle, David B.

N1 - This work was supported by Merial Ltd., The Japan Society for the Promotion of Sciences (KAKENHI, Grant number: 17H01472) and The UK Medical Research Council.

PY - 2018/8

Y1 - 2018/8

N2 - 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.

AB - 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.

KW - Glutamate-gated-chloride channel

KW - Tick Ixodes scapularis

KW - Ivermectin

KW - Okaramine B

KW - Acaricide

U2 - 10.1016/j.ijpddr.2018.06.001

DO - 10.1016/j.ijpddr.2018.06.001

M3 - Article

SN - 2211-3207

VL - 8

SP - 350

EP - 360

JO - International Journal for Parasitology: Drugs and Drug Resistance

JF - International Journal for Parasitology: Drugs and Drug Resistance

IS - 2

ER -

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

Abstract

Keywords

UN SDGs

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