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Induction of apoptosis in macrophages via Kv1.3 and Kv1.5 potassium channels

L Leanza1, M Zoratti, E Gulbins

  • 1Department of Biology, University of Padova, viale G. Colombo 3, 35121, Padova, Italy.

Current Medicinal Chemistry
|August 4, 2012
PubMed

Insights

Kv1.1, Kv1.3, and Kv1.5 potassium channels interact with Bax, influencing apoptosis. Membrane-permeant drugs targeting these mitochondrial channels can induce cell death, offering potential therapeutic strategies for immune cells and tumors.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • The mitochondrial potassium channel Kv1.3 (mtKv1.3) is a target of Bax, and its inhibition is crucial for apoptosis.
  • Bax mutation at lysine 128 (BaxK128E) prevents apoptosis by abrogating mtKv1.3 inhibition.
  • Previous studies showed membrane-permeant Kv1.3 inhibitors induce apoptosis and reduce tumor volume.

Purpose of the Study:

  • To investigate the role of other Kv channels (Kv1.1, Kv1.5) in apoptosis.
  • To determine if the Bax-Kv1.3 interaction mechanism extends to other Kv channels.
  • To explore the therapeutic potential of targeting mitochondrial Kv channels in macrophages.

Main Methods:

  • Investigated interactions between Bax and Kv1.1, Kv1.5 using transfection and siRNA.
  • Assessed apoptosis sensitivity in Kv-deficient and Kv-overexpressing lymphocytes (CTLL-2).
  • Examined mitochondrial Kv1.3 and Kv1.5 expression in J774 macrophages and their response to specific inhibitors.

Main Results:

  • Kv1.1 and Kv1.5, like Kv1.3, interact with Bax.
  • Restoring Kv1.1 in Kv-deficient lymphocytes re-sensitizes them to apoptosis.
  • Down-regulating Kv1.3 and Kv1.5 in macrophages confers apoptosis resistance.
  • Inhibiting mitochondrial Kv1.3 and Kv1.5 in macrophages induces apoptosis.

Conclusions:

  • The mechanism of Bax-mediated apoptosis involving Kv channels extends beyond Kv1.3 to include Kv1.1 and Kv1.5.
  • Membrane-permeant drugs targeting mitochondrial Kv channels are effective in inducing apoptosis in macrophages.
  • This approach may offer a novel pharmacological strategy for depleting tumor-associated macrophages, potentially inhibiting tumor growth.

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