Functional Characterization of the Oxantel-Sensitive Acetylcholine Receptor from <i>Trichuris muris</i>
The human whipworm, <i>Trichuris trichiura</i>, is estimated to infect 289.6 million people globally. Control of human trichuriasis is a particular challenge, as most anthelmintics have a limited single-dose efficacy, with the striking exception of the narrow-spectrum anthelmintic, oxant...
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MDPI AG
2021-07-01
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| Series: | Pharmaceuticals |
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| author | Tina V. A. Hansen Richard K. Grencis Mohamed Issouf Cédric Neveu Claude L. Charvet |
| author_facet | Tina V. A. Hansen Richard K. Grencis Mohamed Issouf Cédric Neveu Claude L. Charvet |
| author_sort | Tina V. A. Hansen |
| collection | DOAJ |
| description | The human whipworm, <i>Trichuris trichiura</i>, is estimated to infect 289.6 million people globally. Control of human trichuriasis is a particular challenge, as most anthelmintics have a limited single-dose efficacy, with the striking exception of the narrow-spectrum anthelmintic, oxantel. We recently identified a novel ACR-16-like subunit from the pig whipworm, <i>T. suis</i> which gave rise to a functional acetylcholine receptor (nAChR) preferentially activated by oxantel. However, there is no ion channel described in the mouse model parasite <i>T. muris</i> so far. Here, we have identified the ACR-16-like and ACR-19 subunits from <i>T. muris</i>, and performed the functional characterization of the receptors in <i>Xenopus laevis</i> oocytes using two-electrode voltage-clamp electrophysiology. We found that the ACR-16-like subunit from <i>T. muris</i> formed a homomeric receptor gated by acetylcholine whereas the ACR-19 failed to create a functional channel. The subsequent pharmacological analysis of the <i>Tmu</i>-ACR-16-like receptor revealed that acetylcholine and oxantel were equally potent. The <i>Tmu</i>-ACR-16-like was more responsive to the toxic agonist epibatidine, but insensitive to pyrantel, in contrast to the <i>Tsu</i>-ACR-16-like receptor. These findings confirm that the ACR-16-like nAChR from <i>Trichuris</i> spp. is a preferential drug target for oxantel, and highlights the pharmacological difference between <i>Trichuris</i> species. |
| first_indexed | 2024-03-10T09:28:59Z |
| format | Article |
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| language | English |
| last_indexed | 2024-03-10T09:28:59Z |
| publishDate | 2021-07-01 |
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| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-c1621aa011684d0d9705381a2757407b2023-11-22T04:40:25ZengMDPI AGPharmaceuticals1424-82472021-07-0114769810.3390/ph14070698Functional Characterization of the Oxantel-Sensitive Acetylcholine Receptor from <i>Trichuris muris</i>Tina V. A. Hansen0Richard K. Grencis1Mohamed Issouf2Cédric Neveu3Claude L. Charvet4INRAE, Université de Tours, ISP, F-37380 Nouzilly, FranceLydia Becker Institute for Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UKINRAE, Université de Tours, ISP, F-37380 Nouzilly, FranceINRAE, Université de Tours, ISP, F-37380 Nouzilly, FranceINRAE, Université de Tours, ISP, F-37380 Nouzilly, FranceThe human whipworm, <i>Trichuris trichiura</i>, is estimated to infect 289.6 million people globally. Control of human trichuriasis is a particular challenge, as most anthelmintics have a limited single-dose efficacy, with the striking exception of the narrow-spectrum anthelmintic, oxantel. We recently identified a novel ACR-16-like subunit from the pig whipworm, <i>T. suis</i> which gave rise to a functional acetylcholine receptor (nAChR) preferentially activated by oxantel. However, there is no ion channel described in the mouse model parasite <i>T. muris</i> so far. Here, we have identified the ACR-16-like and ACR-19 subunits from <i>T. muris</i>, and performed the functional characterization of the receptors in <i>Xenopus laevis</i> oocytes using two-electrode voltage-clamp electrophysiology. We found that the ACR-16-like subunit from <i>T. muris</i> formed a homomeric receptor gated by acetylcholine whereas the ACR-19 failed to create a functional channel. The subsequent pharmacological analysis of the <i>Tmu</i>-ACR-16-like receptor revealed that acetylcholine and oxantel were equally potent. The <i>Tmu</i>-ACR-16-like was more responsive to the toxic agonist epibatidine, but insensitive to pyrantel, in contrast to the <i>Tsu</i>-ACR-16-like receptor. These findings confirm that the ACR-16-like nAChR from <i>Trichuris</i> spp. is a preferential drug target for oxantel, and highlights the pharmacological difference between <i>Trichuris</i> species.https://www.mdpi.com/1424-8247/14/7/698<i>Trichuris</i>antiparasitic drugsoxantelnAChRhelminthselectrophysiology |
| spellingShingle | Tina V. A. Hansen Richard K. Grencis Mohamed Issouf Cédric Neveu Claude L. Charvet Functional Characterization of the Oxantel-Sensitive Acetylcholine Receptor from <i>Trichuris muris</i> Pharmaceuticals <i>Trichuris</i> antiparasitic drugs oxantel nAChR helminths electrophysiology |
| title | Functional Characterization of the Oxantel-Sensitive Acetylcholine Receptor from <i>Trichuris muris</i> |
| title_full | Functional Characterization of the Oxantel-Sensitive Acetylcholine Receptor from <i>Trichuris muris</i> |
| title_fullStr | Functional Characterization of the Oxantel-Sensitive Acetylcholine Receptor from <i>Trichuris muris</i> |
| title_full_unstemmed | Functional Characterization of the Oxantel-Sensitive Acetylcholine Receptor from <i>Trichuris muris</i> |
| title_short | Functional Characterization of the Oxantel-Sensitive Acetylcholine Receptor from <i>Trichuris muris</i> |
| title_sort | functional characterization of the oxantel sensitive acetylcholine receptor from i trichuris muris i |
| topic | <i>Trichuris</i> antiparasitic drugs oxantel nAChR helminths electrophysiology |
| url | https://www.mdpi.com/1424-8247/14/7/698 |
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