Apoptotic proteins reaper and grim induce stable inactivation in voltage-gated K⁺ channels

Drosophila genes reaper, grim, and head-involution-defective (hid) induce apoptosis in several cellular contexts. N-terminal sequences of these proteins are highly conserved and are similar to N-terminal inactivation domains of voltage-gated potassium (K⁺) channels. Synthetic Reaper and Grim N terminus peptides induced fast inactivation of Shaker-type K⁺ channels when applied to the cytoplasmic side of the channel that was qualitatively similar to the inactivation produced by other K⁺ channel inactivation particles. Mutations that reduce the apoptotic activity of Reaper also reduced the synthetic peptide's ability to induce channel inactivation, indicating that K⁺ channel inactivation correlated with apoptotic activity. Coexpression of Reaper RNA or direct injection of full length Reaper protein caused near irreversible block of the K⁺ channels. These results suggest that Reaper and Grim may participate in initiating apoptosis by stably blocking K⁺ channels.