Molecular and structural determinants that contribute to channel function and gating in channelrhodopsin-2

Richards, Ryan

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Molecular and structural determinants that contribute to channel function and gating in channelrhodopsin-2

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The green algae Chlamydomonas reinhardtii senses light through two photosensory proteins, channelrhodopsin-1 (ChR1) and channelrhodopsin-2 (ChR2). The initial discovery of these two photoreceptors introduced a new class of light-gated ion channels. ChR2 is an inwardly-rectified ion channel that is selective for cations of multiple valencies. Similar to microbial-rhodopsin ion pumps, ChR2 has a seven transmembrane domain motif that binds the chromophore all-trans retinal through a protonated Schiff base linkage. Physiologically, ChR2 functions to depolarize the membrane which initiates a signaling cascade triggering phototactic response. This fundamental property has been pivotal in pioneering the field of optogenetics, where excitable cells can be manipulated by light. ChR2 reliably causes neuronal spiking with high spatial and temporal control. Moreover, the recent discovery of new chloride-conducting channelrhodopsins (ChloCs) has further expanded the optogenetic toolbox. Although structurally similar to microbial-rhodopsin ion pumps, ChR2 undergoes more complex conformational rearrangements that lead to ion conductance. Currently, the molecular basis for ChR2 gating remains unresolved. Revealing the specific structural interactions that modulate ChR2 function have important implications in understanding the intricacies of ion transport and molecular differences between ion pumps, channels, and transporters. Here we describe a combined computational and experimental approach to elucidate the mechanism of ion conductance, channel gating, and structure-function relationship of ChR2. Our results have contributed to expanding our understanding of the fundamental properties of ion channels.

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