Voriconazole, an antifungal triazol that causes visual side effects, is an inhibitor of TRPM1 and TRPM3 channels.
Voriconazole, an antifungal triazol that causes visual side effects, is an inhibitor of TRPM1 and TRPM3 channels.
复制标题
伏立康唑是一种抗真菌三唑，会引起视觉副作用，是 TRPM1 和 TRPM3 通道的抑制剂。
DOI：
10.1167/iovs.14-15270
复制
发表时间：
2015
影响因子：
4.4
通讯作者：
Morgans,CatherineW
中科院分区：
文献类型：
--
作者：
Xiong,Wei-Hong;Brown,RLane;Reed,Brian;Burke,NealS;Duvoisin,RobertM;Morgans,CatherineW
目的。伏立康唑是一种抗真菌的三唑类药物，可引起患者短暂的视觉障碍，并减弱ERG的b波。我们试图确定伏立康唑对ERG b波影响的视网膜靶点。记录小鼠腹腔注射伏立康唑前后视网膜电图。采用膜片钳法记录小鼠视网膜on -bipolar细胞切片，检测伏立康唑对on -bipolar细胞的影响。通过膜片钳记录TRPM3或mGluR6 + Kir3转染的中国仓鼠卵巢（CHO）和HEK293细胞，评估伏立康唑对mGluR6和TRPM3的影响。1 / Kir3。4.的结果。伏立康唑能减弱小鼠ERG b波，抑制mGluR6拮抗剂CPPG作用于ON-bipolar细胞树突引起的ON-bipolar细胞反应，表明伏立康唑阻断了mGluR6- trpm1信号转导通路中的一个步骤。伏立康唑几乎完全阻断了on双极细胞中辣椒素激活的电流，这归因于TRPM1阳离子通道的直接激活。此外，将伏立康唑应用于表达TRPM3（与TRPM1密切相关的通道）的CHO细胞，发现伏立康唑可逆地阻断了转染细胞中孕烯醇酮刺激的TRPM3电流。相比之下，伏立康唑仅能轻微抑制共转染细胞中mGluR6介导的g蛋白激活内向整流钾（GIRK）电流的激活，这表明mGluR6不是伏立康唑在on -双极细胞中的主要靶点。结论：伏立康唑引起的视觉障碍可能是由于视网膜on -双极细胞中TRPM1通道的阻断。伏立康唑的其他神经学作用可能是由于阻断大脑中表达的TRPM3通道。
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.