Wei-Hong Xiong1, R Lane Brown2, Brian Reed2, Neal S Burke2, Robert M Duvoisin1, Catherine W Morgans1. 1. Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon, United States. 2. Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington, United States.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.
PURPOSE: 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. METHODS: 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. RESULTS: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. CONCLUSIONS: 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. Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.
Authors: Thaddeus P Dryja; Terri L McGee; Eliot L Berson; Gerald A Fishman; Michael A Sandberg; Kenneth R Alexander; Deborah J Derlacki; Aruna S Rajagopalan Journal: Proc Natl Acad Sci U S A Date: 2005-03-21 Impact factor: 11.205
Authors: Christina Zeitz; Maria van Genderen; John Neidhardt; Ulrich F O Luhmann; Frank Hoeben; Ursula Forster; Katharina Wycisk; Gábor Mátyás; Carel B Hoyng; Frans Riemslag; Françoise Meire; Frans P M Cremers; Wolfgang Berger Journal: Invest Ophthalmol Vis Sci Date: 2005-11 Impact factor: 4.799
Authors: Joseph M Harrison; Randolph D Glickman; Charles S Ballentine; Yolanda Trigo; Melanie A Pena; Pearl Kurian; Laura K Najvar; Neeru Kumar; Ankit H Patel; William E Sponsel; John R Graybill; William C Lloyd; Margaret M Miller; Gianmarco Paris; Fernando Trujillo; Aaron Miller; Robert Melendez Journal: Doc Ophthalmol Date: 2005-01 Impact factor: 2.379
Authors: Hua Gao; Mark E Pennesi; Kekul Shah; Xiaoxi Qiao; Seenu M Hariprasad; William F Mieler; Samuel M Wu; Eric R Holz Journal: Arch Ophthalmol Date: 2004-11
Authors: Thomas Colley; Gurpreet Sehra; Anuradha Chowdhary; Alexandre Alanio; Steven L Kelly; Yasuo Kizawa; Darius Armstrong-James; Matthew C Fisher; Andrew G S Warrilow; Josie E Parker; Diane E Kelly; Genki Kimura; Yuki Nishimoto; Mihiro Sunose; Stuart Onions; Damien Crepin; Franz Lagasse; Matthew Crittall; Jonathan Shannon; Matthew McConville; John King-Underwood; Alan Naylor; Stéphane Bretagne; John Murray; Kazuhiro Ito; Pete Strong; Garth Rapeport Journal: Antimicrob Agents Chemother Date: 2018-04-26 Impact factor: 5.191