Ultra light-sensitive and fast neuronal activation with the Ca-permeable Channelrhodopsin CatCh

The light-gated cation channel channelrhodopsin-2 (ChR2) has rapidly become a principal tool in neuroscience and its use is currently considered in multiple therapeutic interventions. Although wild-type and known variant ChR2s are able to drive light-activated spike trains, their use in potential clinical applications is limited either by low light-sensitivity or slow channel kinetics. Here we present a new variant, CatCh, mediating accelerated response time and a voltage response that is ~70-fold more light-sensitive than that of wild-type. We show that CatCh's superior properties stem from its enhanced Ca-permeability. An increase in [Ca] elevates the internal surface potential, facilitating activation of voltage-gated Na-channels and indirectly increasing light-sensitivity. Repolarization following light-stimulation is markedly accelerated by Ca-dependent BK-channel activation. Our results demonstrate a new principle, shifting permeability from monovalent to divalent cations, to increase sensitivity without compromising fast kinetics of neuronal activation. This paves the way for clinical use of light-gated channels.