Referenced in: none

Automatically associated channels: Kir3.1 , Kir3.4 , TRP , TRPM , TRPM1 , TRPM3

Title: Voriconazole, an antifungal triazol that causes visual side effects, is an inhibitor of TRPM1 and TRPM3 channels.

Authors: Wei-Hong Xiong, R Lane Brown, Brian Reed, Neal S Burke, Robert M Duvoisin, Catherine W Morgans

Journal, date & volume: Invest. Ophthalmol. Vis. Sci., 2015 Feb , 56, 1367-73

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25650413

Abstract
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.