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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,8,23]]},"abstract":"<jats:p>\n                    Glutamate-gated chloride channels (GluCls) are unique to invertebrates and are targeted by macrocyclic lactones. In this study, we cloned an AVR-14B GluCl subunit from adult\n                    <jats:italic>Brugia malayi<\/jats:italic>\n                    , a causative agent of lymphatic filariasis in humans. To elucidate this channel\u2019s pharmacological properties, we used\n                    <jats:italic>Xenopus laevis<\/jats:italic>\n                    oocytes for expression and performed two-electrode voltage-clamp electrophysiology. The receptor was gated by the natural ligand L-glutamate (effective concentration, 50% [\n                    <jats:italic>\n                      EC\n                      <jats:sub>50<\/jats:sub>\n                    <\/jats:italic>\n                    ] = 0.4 mM) and ivermectin (IVM;\n                    <jats:italic>\n                      EC\n                      <jats:sub>50<\/jats:sub>\n                    <\/jats:italic>\n                    = 1.8 nM). We also characterized the effects of nodulisporic acid (NA) on\n                    <jats:italic>Bma<\/jats:italic>\n                    -AVR-14B and NA-produced dual effects on the receptor as an agonist and a type II positive allosteric modulator. Here we report characterization of the complex activity of NA on a nematode GluCl.\n                    <jats:italic>Bma<\/jats:italic>\n                    -AVR-14B demonstrated some unique pharmacological characteristics. IVM did not produce potentiation of L-glutamate\u2013mediated responses but instead, reduced the channel\u2019s sensitivity for the ligand. Further electrophysiological exploration showed that IVM (at a moderate concentration of 0.1 nM) functioned as an inhibitor of both agonist and positive allosteric modulatory effects of NA. This suggests that IVM and NA share a complex interaction. The pharmacological properties of\n                    <jats:italic>Bma<\/jats:italic>\n                    -AVR-14B indicate that the channel is an important target of IVM and NA. In addition, the unique electrophysiological characteristics of\n                    <jats:italic>Bma<\/jats:italic>\n                    -AVR-14B could explain the observed variation in drug sensitivities of various nematode parasites. We have also shown the inhibitory effects of IVM and NA on adult worm motility using Worminator. RNA interference (RNAi) knockdown suggests that AVR-14 plays a role in influencing locomotion in\n                    <jats:italic>B. malayi<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1073\/pnas.2111932119","type":"journal-article","created":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T15:21:26Z","timestamp":1660576886000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":7,"title":["Nodulisporic acid produces direct activation and positive allosteric modulation of AVR-14B, a glutamate-gated chloride channel from adult\n                    <i>Brugia malayi<\/i>"],"prefix":"10.1073","volume":"119","author":[{"given":"Shivani","family":"Choudhary","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 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50011"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Kulke","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 50011"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2422-1847","authenticated-orcid":false,"given":"Richard J.","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 50011"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7980-1139","authenticated-orcid":false,"given":"Alan P.","family":"Robertson","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 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