Bernal Sierra, Y. A. et al. Nat. Commun. 9, 4611 (2018).

Alberio, L. et al. Nat. Methods 15, 969–976 (2018).

Channelrhodopsin is a widely used optogenetic activator, but despite the availability of a few inhibitory optogenetic tools, a clear consensus on the most suitable tool remains to be reached. Bernal Sierra et al. report a two-component system for optogenetic inhibition. For their PAC-K tool, the researchers combined the photoactivatable nucleotidyl cyclase bPAC with the cyclic nucleotide-gated potassium channel SthK. These microbial proteins are small and express well in mammalian cells. PAC-K and the recently described BLINK2 channel (Alberio et al.) modulate the potassium gradient across the cell membrane, which provides advantages over other inhibitory tools that change intracellular chloride or proton levels and can cause paradoxical effects. Bernal Sierra et al. found that they could elicit strong outward currents upon expression of the PAC-K tool in cardiomyocytes, and that inhibition depended on illumination intensity. PAC-K also efficiently silenced neurons in the mouse hippocampus and in zebrafish larvae.