Voriconazole, an Antifungal Triazol That Causes Visual Side Effects, Is an Inhibitor of TRPM1 and TRPM3 Channels
| Autor: | Robert M. Duvoisin, Brian T. Reed, R. Lane Brown, Wei Hong Xiong, Neal S. Burke, Catherine W. Morgans |
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| Rok vydání: | 2015 |
| Předmět: |
Antifungal Agents
Visual acuity genetic structures Visual Acuity Triazole TRPM Cation Channels Dark Adaptation Pharmacology Biology Mice Cellular and Molecular Neuroscience chemistry.chemical_compound Retinal Diseases Cricetinae Electroretinography medicine Animals TRPM3 Cells Cultured TRPM1 Voriconazole medicine.diagnostic_test Retinal Articles eye diseases Sensory Systems Disease Models Animal Ophthalmology chemistry Female sense organs medicine.symptom Erg medicine.drug |
| Zdroj: | Investigative Ophthalmology & Visual Science. 56:1367-1373 |
| ISSN: | 0146-0404 |
| DOI: | 10.1167/iovs.14-15270 |
| Popis: | Administration of voriconazole, an antifungal triazole, causes transient visual disturbances in patients and attenuates the b-wave of the ERG. We sought to identify the retinal target of voriconazole underlying the effect on the ERG b-wave.Electroretinograms were recorded from mice before and after intraperitoneal injection of voriconazole. The effect of voriconazole on ON-bipolar cells was tested by patch-clamp recordings of ON-bipolar cells in mouse retinal slices. Effects of voriconazole on mGluR6 and TRPM3 were assessed by patch-clamp recordings of Chinese hamster ovary (CHO) and HEK293 cells transfected with either TRPM3 or mGluR6 plus Kir3.1/Kir3.4.Voriconazole attenuated the ERG b-wave in mice, and inhibited ON-bipolar cell responses evoked by application of CPPG, an mGluR6 antagonist, onto the ON-bipolar cell dendrites, indicating that voriconazole blocks a step in the mGluR6-TRPM1 signal transduction pathway. Voriconazole almost completely blocked capsaicin-activated currents in ON-bipolar cells, which have been attributed to direct activation of the TRPM1 cation channel. Furthermore, application of voriconazole to CHO cells expressing TRPM3, a closely related channel to TRPM1, showed that voriconazole reversibly blocked pregnenolone sulfate-stimulated TRPM3 currents in transfected cells. In contrast, voriconazole only slightly inhibited mGluR6-mediated activation of G-protein activated inward rectifier potassium (GIRK) currents in cotransfected cells, suggesting that mGluR6 is not the primary target of voriconazole in ON-bipolar cells.The visual disturbances associated with voriconazole are likely due to block of TRPM1 channels in retinal ON-bipolar cells. Other neurological effects of voriconazole may be due to block of TRPM3 channels expressed in the brain. |
| Databáze: | OpenAIRE |
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