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bioRxiv · 10.64898/2026.07.22.740102

A highly Ca2+-permeable channelrhodopsin from the ancyromonad Nutomonas longa enables optogenetic control of Ca2+ signaling

Govorunova, E. G.·Gou, Y.·McDonald, A. J.·Sineshchekov, O. A.·Li, H.·Wang, Y.·St-Pierre, F.·Xue, M.·Spudich, J. L.
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Abstract

Ca{superscript 2} is a ubiquitous regulator of cellular function, linking electrical activity to gene expression, secretion, metabolism, and synaptic plasticity. Yet, tools for its direct, time-resolved optical manipulation remain limited. Here, we report that NlCCR, a channelrhodopsin from Nutomonas longa, possesses high Ca{superscript 2} permeability, enabling precise optical control of Ca{superscript 2} signaling. Compared with CapChR2, the most potent engineered Ca{superscript 2}-conducting channelrhodopsin, NlCCR combines larger and faster photocurrents, higher Ca{superscript 2} permeability, weaker desensitization, and reduced inward rectification. Mutational analysis identified determinants of Ca{superscript 2} selectivity and further enhanced it by introducing carboxylate residues at the channels central gate. NlCCRs blue-shifted absorption (445 nm) minimized optical crosstalk with a red-shifted Ca{superscript 2} indicator, laying the groundwork for all-optical experiments. In mouse cortical pyramidal neurons, NlCCR enabled synaptic transmission independently of endogenous voltage-gated Ca{superscript 2} channels. These findings establish NlCCR as a broadly applicable tool for direct, temporally precise manipulation of Ca{superscript 2}-dependent signaling in living systems.

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Govorunova, E. G., Gou, Y., McDonald, A. J., Sineshchekov, O. A., Li, H., Wang, Y., St-Pierre, F., Xue, M., Spudich, J. L.. 2026-07-27. A highly Ca2+-permeable channelrhodopsin from the ancyromonad Nutomonas longa enables optogenetic control of Ca2+ signaling. https://doi.org/10.64898/2026.07.22.740102

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