Abstract
The voltage-gated potassium channel Kv1.3 plays an apparent dual physiological role by participating in activation and proliferation of leukocytes as well as promoting apoptosis in several types of tumor cells. Therefore, Kv1.3 is considered a potential pharmacological target for immunodeficiency and cancer. Different cellular locations of Kv1.3, at the plasma membrane or the mitochondria, could be responsible for such duality. While plasma membrane Kv1.3 facilitates proliferation, the mitochondrial channel modulates apoptotic signaling. Several molecular determinants of Kv1.3 drive the channel to the cell surface, but no information is available about its mitochondrial targeting. Caveolins, which are able to modulate cell survival, participate in the plasma membrane targeting of Kv1.3. The channel, via a caveolin-binding domain (CDB), associates with caveolin 1 (Cav1), which localizes Kv1.3 to lipid raft membrane microdomains. The aim of our study was to understand the role of such interactions not only for channel targeting but also for cell survival in mammalian cells. By using a caveolin association-deficient channel (Kv1.3 CDBless), we demonstrate here that while the Kv1.3-Cav1 interaction is responsible for the channel localization in the plasma membrane, a lack of such interaction accumulates Kv1.3 in the mitochondria. Kv1.3 CDBless severely affects mitochondrial physiology and cell survival, indicating that a functional link of Kv1.3 with Cav1 within the mitochondria modulates the pro-apoptotic effects of the channel. Therefore, the balance exerted by these two complementary mechanisms fine-tune the physiological role of Kv1.3 during cell survival or apoptosis. Our data highlight an unexpected role for the mitochondrial caveolin-Kv1.3 axis during cell survival and apoptosis.
Highlights
The voltage-gated potassium channel Kv1.3 is present at the plasma membrane of different cell types, mostly neurons and leukocytes (Cahalan and Chandy, 2009; Martınez-Marmol et al, 2016; Soleet al., 2016)
We have previously described that the interaction between Kv1.3 and caveolin 1 (Cav1) results in the localization of the channel to lipid rafts and caveolae (Perez-Verdaguer et al, 2016a; Perez-Verdaguer et al, 2018)
Caveolin is involved in both pro- and anti-apoptotic events participating in the regulation of cell survival and in cancer protection
Summary
The voltage-gated potassium channel Kv1.3 is present at the plasma membrane of different cell types, mostly neurons and leukocytes (Cahalan and Chandy, 2009; Martınez-Marmol et al, 2016; Soleet al., 2016). Kv1.3 is efficiently expressed on the cell surface, which depends on multiple forward trafficking signatures located at the C-terminal domain of the channel (Martınez-Marmol et al, 2013). Different ancillary interactions modulate the trafficking of Kv1.3 (Capera et al, 2019). The Kv1.5 channel and the regulatory KCNE4 subunit retain Kv1.3 at the endoplasmic reticulum (ER), negatively modulating the channel surface expression (Vicente et al, 2006; Vicente et al, 2008; Soleet al., 2009). The scaffolding protein caveolin 1 (Cav1) controls Kv1.3 spatial localization in raft microdomains, which is important for signaling and cell physiology (Perez-Verdaguer et al, 2016a; Perez-Verdaguer et al, 2018)
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