كتاب
A novel receptor target for old anthelmintic drugs evaluated in the nematode Caenorhabditis elegans
| العنوان: | A novel receptor target for old anthelmintic drugs evaluated in the nematode Caenorhabditis elegans |
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| المؤلفون: | Rodriguez Araujo, Noelia, Hernando, Guillermina Silvana, Corradi, Jeremias, Bouzat, Cecilia Beatriz |
| المساهمون: | Delfino, Jose Maria |
| بيانات النشر: | Sociedad Argentina de Biofísica |
| المجموعة: | CONICET Digital (Consejo Nacional de Investigaciones Científicas y Técnicas) |
| مصطلحات موضوعية: | CHLORIDE CHANNEL, ANTHELMINTIC THERAPY, CAENORHABDITIS ELEGANS, DRUG TARGET, https://purl.org/becyt/ford/1.6Test, https://purl.org/becyt/ford/1Test |
| جغرافية الموضوع: | Internacional |
| الوصف: | Ivermectin (IVM) and piperazine (PZE), which are agonists of Glutamate-gated chloride channels and GABAA receptors, respectively, are marketed drugs used in anthelmintic therapy. Here we discovered a novel target of these drugs by evaluating their effects on the free-living nematode C. elegans. Nematodes contain a homomeric 5HT-gated chloride channel, MOD-1, that modulates locomotor behavior. Due to its absence in vertebrates, MOD-1 emerges as an attractive anthelmintic drug target. By electrophysiological recordings from cells expressing MOD-1, we deciphered its pharmacological properties and searched for novel ligands. Macroscopic currents activated by 5-HT showed that MOD-1 desensitizes slowly and recovers from desensitization in about 1 s. Dose-response curves revealed an EC50 for 5-HT of ~1 μM, similar to that of 5-HT3A receptors. The partial agonists tryptamine and 2-Me-5HT showed very different efficacies between MOD-1 and 5-HT3A receptors. IVM and PZE did not activate MOD-1 but acted as non-competitive antagonists. IVM produced a slight and irreversible inhibition whereas PZE led to a profound and reversible inhibition, indicating that MOD-1 may be involved in their anthelmintic effects. Also, the specific GABAA receptor agonists, muscimol and isoguvacine, inhibited MOD-1 currents. We performed locomotor activity assays of wild- type (WT) and mutant strains to establish MOD-1 as a novel anthelmintic target. We found that 5-HT produced a rapid paralysis of WT worms while the MOD-1 mutant strain was resistant, thus confirming MOD-1 as the functional target of 5-HT. The exposure of worms to 5-HT combined with IVM or PZE at concentrations at which they do not act at their canonical receptors reduced the 5-HT paralyzing effect, thus supporting the negative modulation of MOD-1 detected in electrophysiological recordings. This study contributes to our understanding of the action of drugs to treat parasitic diseases and to guide future drug discovery efforts. ; Fil: Rodriguez Araujo, Noelia. Consejo Nacional de ... |
| نوع الوثيقة: | book conference object |
| وصف الملف: | application/pdf; application/vnd.openxmlformats-officedocument.wordprocessingml.document |
| اللغة: | English |
| ردمك: | 978-987-27591-9-3 987-27591-9-7 |
| العلاقة: | info:eu-repo/semantics/altIdentifier/url/https://biofisica.org.ar/reuniones-cientificas/reunionsab-previasTest/; http://hdl.handle.net/11336/176090Test; A novel receptor target for old anthelmintic drugs evaluated in the nematode Caenorhabditis elegans; XLIX Reunión Anual de la Sociedad Argentina de Biofísica; Argentina; 2021; 71-71; CONICET Digital; CONICET |
| الإتاحة: | http://hdl.handle.net/11336/176090Test |
| حقوق: | info:eu-repo/semantics/openAccess ; https://creativecommons.org/licenses/by-nc-sa/2.5/arTest/ |
| رقم الانضمام: | edsbas.4B1DB410 |
| قاعدة البيانات: | BASE |
| ردمك: | 9789872759193 9872759197 |
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