Unifying photocycle model for light adaptation and temporal evolution of cation conductance in channelrhodopsin-2

Significance Understanding the mechanisms of photoactivated biological processes facilitates the development of new molecular tools, engineered for specific optogenetic applications, allowing the control of neuronal activity with light. Here, we use a variety of experimental and theoretical techniques to examine the precise nature of the light-activated ion channel in one of the most important molecular species used in optogenetics, channelrhodopsin-2. Existing models for the photochemical and photophysical pathway after light absorption by the molecule fail to explain many aspects of its observed behavior, including the inactivation of the photocurrent under continuous illumination. We resolve this by proposing a branched photocycle explaining electrical and photochemical channel properties and establishing the structure of intermediates during channel turnover.