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Ultra light-sensitive and fast neuronal activation with the Ca2+-permeable channelrhodopsin CatCh


The light-gated cation channel channelrhodopsin-2 (ChR2) has rapidly become an important tool in neuroscience, and its use is being considered in 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 by either low light sensitivity or slow channel kinetics. We present a new variant, calcium translocating channelrhodopsin (CatCh), which mediates an accelerated response time and a voltage response that is 70-fold more light sensitive than that of wild-type ChR2. CatCh's superior properties stem from its enhanced Ca2+ permeability. An increase in [Ca2+]i 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 Ca2+-dependent BK channel activation. Our results demonstrate a previously unknown 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.

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Figure 1: Homology model of ChR2 based on the sensory rhodopsin 2 structure (PDB accession number 1H2S).
Figure 2: Biophysical characterization of CatCh in HEK293 cells and Xenopus oocytes.
Figure 3: CatCh expression in hippocampal cultured neurons.
Figure 4: Fast and high-sensitivity neural photostimulation.


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We would like to thank I. Bartnik for the preparation of the hippocampal neuron cultures, S. O'Shea for the help with the calcium imaging experiments, V. Busskamp for the support in recombinant adeno-associated virus construction, H. Biehl for excellent technical assistance, and K. Hartung, H. Spors, U. Terpitz and M. van Wyk for helpful discussions. The work was supported by grants from the Deutsche Forschungsgemeinschaft Sonderforschungsbereich 807, Centre of Excellence Frankfurt Macromolecular Complexes and the Federal Ministry of Education and Research of Germany (01GQ0815) to E.B., and by the Max Planck Society.

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S.K., R.E.D., P.G.W. and E.B. conceived the experiments. S.K., K.F., H.F. and C.B. carried out the experiments. S.K., C.B. and K.F. performed the data analysis. S.K., C.B. and E.B. wrote the manuscript.

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Correspondence to Ernst Bamberg.

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The authors declare no competing financial interests.

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Kleinlogel, S., Feldbauer, K., Dempski, R. et al. Ultra light-sensitive and fast neuronal activation with the Ca2+-permeable channelrhodopsin CatCh. Nat Neurosci 14, 513–518 (2011).

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