Induction of Apoptosis in Macrophages via Kv1.3 and Kv1.5 Potassium Channels

L.      Leanza; M.      Zoratti; E.      Gulbins; I.      Szabo

Abstract

We have previously shown that the mitochondrial potassium channel Kv1.3 (mtKv1.3) in T lymphocytes is a novel target of Bax. Mutation of Bax at lysine 128 (BaxK128E) abrogates its inhibitory effects on mtKv1.3 and prevents apoptosis. The importance of mtKv1.3 inhibition was underscored by the finding that membrane-permeant Kv1.3 inhibitors induced Bax/Bak-independent cell death and reduced the volume of an mtKv1.3-expressing tumor by 90% in a mouse model. However, the possible involvement of other Kv channels in apoptosis has not been clarified. Here we report that, like Kv1.3, Kv1.1 and Kv1.5 also interact with Bax. Transfection of Kvdeficient lymphocytes with Kv1.1 restores sensitivity to cell death in apoptosis-resistant CTLL-2 lymphocytes. SiRNA down-regulation of Kv1.3 and Kv1.5 expression in macrophages confers resistance to apoptosis. We further report that J774 macrophages express Kv1.3 and Kv1.5 in their mitochondria and that inhibition of both channels with specific membrane-permeant drugs can efficiently induce apoptosis in a macrophage cell line. Thus, our results indicate that the mechanism proposed for Kv1.3 can be extended to other Kv channels and suggest that membrane-permeant drugs may be a novel pharmacological tool for inducing apoptosis in macrophages, important players in the immune system. This result could be exploited for the depletion of tumor-associated macrophages, which have been shown to foster tumor growth.

Keywords: Apoptosis, ion channels, Kv1.3 inhibitors, Kv1.5 potassium channel, macrophage, mitochondria, mitochondrial potassium, T lymphocytes, membrane-permeant drugs, Kv channels