Apoptotic proteins Reaper and Grim induce stable inactivation in voltage-gated K ⁺ channels

Abstract

Drosophila genes reaper, grim, and headinvolution-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.

Expression and significance of HERG protein in gastric cancer

“…Fas receptor-mediated inhibition of Kv1.3 channels may influence apoptosis in the human leukemic T-cell line Jurkat and two apoptotic proteins, Reaper and Grim, are thought to facilitate apoptosis by stably blocking Kv channels. 21,22 In both studies, the interpretation was that inhibiting potassium channels depolarizes the cells and initiates a caspase-dependent apoptotic pathway. Some authors attributed the effect of potassium channels on apoptosis to the changes of osmolarity and cell volume induced by the potassium currents.…”

BCL-2 family members and the mitochondria in apoptosis

“…In this respect, it is interesting to note that calcium inhibits the BCL-X L channel activity in vitro (Lam et al 1998). Moreover, the pro-apoptotic Drosophila proteins, Reaper and Grim, have been shown capable of inactivating the voltage-gated K + channels (Avdonin et al 1998). An understanding of the serial time course of ionic events that occur across the mitochondrial membrane following the targeting of pro-apoptotic molecules may provide further insight into the essential events.…”

IAP family proteins---suppressors of apoptosis

“…Other mechanisms, however, may be involved in apoptosis induced by HID, GRIM, and RPR, including effects on voltage-gated potassium (K + ) channels (Avdonin et al 1998) and through interactions with another apoptosis-modulating protein called SCYTHE (Thress et al 1998). If RPR, HID, and GRIM do trigger apoptosis through effects on K + channels or interactions with SCYTHE, these events must nevertheless result in caspase activation as p35 potently suppresses apoptosis induced by these Drosophila death proteins, both in cell culture models and in transgenic flies.…”