Van Gelder Russell N
Department of Ophthalmology, University of Washington School of Medicine, United States; Department of Pathology, University of Washington School of Medicine, United States; Department of Biological Structure, University of Washington School of Medicine, United States.
Vision Res. 2015 Jun;111(Pt B):134-41. doi: 10.1016/j.visres.2015.02.001. Epub 2015 Feb 11.
Photoswitches are traditional pharmacologic agonists, antagonists, or channel blockers that are covalently modified with an azobenzene derivative. Azobenzene undergoes wavelength-dependent isomerization between cis and trans conformation. For some photoswitches, only one of these configurations is biologically active, resulting in light-dependent activation or inhibition of function. Photoswitches that feature a quaternary ammonium coupled to the azobenzene moiety cause light-dependent neuronal depolarization due to blockage of voltage-gated potassium channels. Two photoswitch strategies have been pursued. In the one-component strategy, the photoswitch is applied to native receptors; in the two-component strategy, the photoswitch is combined with virally-mediated expression of a genetically modified receptor, to which the photoswitch may covalently bind. The former approach is simpler but the latter allows precise anatomic targeting of photoswitch activity. Acrylamide-azobenzene-quaternary ammonium (AAQ) is the prototypical first-generation one-component photoswitch. When applied to retinas with outer retinal degeneration, ganglion cell firing occurs in response to blue light, and is abrogated by green light. In vivo, AAQ restored pupillary light responses and behavioral light responses in blind animals. DENAQ is a prototypical second generation one-component photoswitch. It features spontaneous thermal relaxation so cell firing ceases in dark, and features a red-shifted activation spectrum. Interestingly, DENAQ only photoswitches in retinas with outer retinal degeneration. MAG is a photoswitched glutamate analog which covalently binds to a modified ionotropic glutamate receptor, LiGluR. When applied together, MAG and LiGluR also rescue physiologic and behavioral light responses in blind mice. Together, photoswitch compounds offer a potentially useful approach to restoration of vision in outer retinal degeneration.
光开关是通过偶氮苯衍生物进行共价修饰的传统药理学激动剂、拮抗剂或通道阻滞剂。偶氮苯在顺式和反式构象之间发生波长依赖性异构化。对于某些光开关，这些构型中只有一种具有生物活性，从而导致功能的光依赖性激活或抑制。具有与偶氮苯部分偶联的季铵盐的光开关由于电压门控钾通道的阻断而导致光依赖性神经元去极化。人们采用了两种光开关策略。在单组分策略中，光开关应用于天然受体；在双组分策略中，光开关与病毒介导的转基因受体表达相结合，光开关可与该受体共价结合。前一种方法更简单，但后一种方法允许对光开关活性进行精确的解剖学靶向。丙烯酰胺-偶氮苯-季铵盐（AAQ）是典型的第一代单组分光开关。当应用于患有外视网膜变性的视网膜时，神经节细胞在蓝光刺激下放电，并在绿光刺激下消失。在体内，AAQ恢复了盲动物的瞳孔光反应和行为光反应。DENAQ是典型的第二代单组分光开关。它具有自发的热弛豫，因此细胞在黑暗中停止放电，并且具有红移的激活光谱。有趣的是，DENAQ仅在患有外视网膜变性的视网膜中起光开关作用。MAG是一种光开关化的谷氨酸类似物，可与修饰的离子型谷氨酸受体LiGluR共价结合。当一起应用时，MAG和LiGluR也能挽救盲鼠的生理和行为光反应。总之，光开关化合物为外视网膜变性的视力恢复提供了一种潜在有用的方法。
