Discovery and design of photocyclic animal opsins: potential application to gene therapy from non-visual opsin research.

Opsins are universal photoreceptive proteins in animals. Rhodopsin is the best-studied opsin and functions as a visual sensor in rod cells of human and mouse retinas. Rhodopsin produces an active state upon photoreception, which triggers the signal transduction cascade to evoke a hyperpolarizing response of the cells. This active state is a metastable intermediate and cannot convert back to the dark state by either photoreaction or thermal reaction. Thus, vertebrate rhodopsin is categorized as a mono-stable opsin. Recent accumulation of genomic information in animals has expanded the known repertoires of opsin genes, which are responsible for visual and non-visual photoreceptive functions. The analysis of these opsins revealed that many opsins, including non-visual opsins such as Opn4 and Opn5, form a stable active state upon photoreception and this active state can photo-convert back to the dark state. These opsins have the property of photoreversibility between the dark and active states and thus are categorized as bistable opsins. In addition, we previously identified a different type of non-visual opsin, Opn5L1, whose activity is controlled by a photocyclic reaction. This photocyclic reaction is quite similar to that of channelrhodopsin and is achieved by a special mechanism involving a cysteine residue at position 188 that has not been observed in any other opsins so far. This review would like to focus on the unique photocyclic animal opsin in the context of the diversity of visual and non-visual opsins and also discuss the possibility of designing "artificial photocyclic opsins" from natural opsins for potential application in optogenetic gene therapy.