title: Voriconazole, an antifungal triazol that causes visual side effects, is an inhibitor of TRPM1 and TRPM3 channels.
abstract: OBJECTIVE
  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.
authors: Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon, United States.
authors: Wei-Hong
authors: WH
authors: Xiong
authors: Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington, United States.
authors: R Lane
authors: RL
authors: Brown
authors: Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington, United States.
authors: Brian
authors: B
authors: Reed
authors: Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington, United States.
authors: Neal S
authors: NS
authors: Burke
authors: Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon, United States.
authors: Robert M
authors: RM
authors: Duvoisin
authors: Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon, United States.
authors: Catherine W
authors: CW
authors: Morgans
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000633:toxicity; D002478:Cells, Cultured; D006224:Cricetinae; D003623:Dark Adaptation / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004596:Electroretinography; D005260:Female; D051379:Mice; D012164:Retinal Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014792:Visual Acuity / Q000187:drug effects*; D065819:Voriconazole / Q000633:toxicity*
chemical_list: D000935:Antifungal Agents; D050053:TRPM Cation Channels; C533868:TRPM3 protein, mouse; C116297:Trpm1 protein, mouse; D065819:Voriconazole
keywords: TRPM1; b-wave; bipolar cell; mGluR6; voriconazole
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