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Mediation of neuronal apoptosis by Kv2.1-encoded potassium channels
Sumon Pal1, Karen A Hartnett, Jeanne M Nerbonne
1Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Abstract:
Cellular K+ efflux is a requisite event in the unfolding of apoptosis programs across many types of cells and death-inducing stimuli; however, the molecular identities of the ion channels mediating this key event have remained undefined. Here, we show that Kv2.1-encoded K+ channels are responsible for the expression of apoptosis in cortical neurons in vitro. Transient expression of two different dominant-negative forms of this subunit in neurons completely eliminated the enhancement of K+ currents that normally accompanies the cell death process. Importantly, neurons deficient in functional Kv2.1-encoded K+ channels were protected from oxidant and staurosporine-induced apoptosis. Finally, Chinese hamster ovary cells, which do not express endogenous voltage-gated K+ channels, became substantially more sensitive to apoptosis after transient expression of wild-type Kv2.1. These results suggest that Kv2.1-encoded K+ channels are necessary for the apoptotic signaling cascade in mammalian cortical neurons in culture and are sufficient for increasing the susceptibility to apoptogens in a nonexcitable cell.
Insights
Kv2.1 potassium channels are essential for apoptosis in cortical neurons. Blocking these channels protects neurons from cell death, while their presence sensitizes other cells to apoptosis.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Cellular potassium (K+) efflux is crucial for apoptosis across various cell types and stimuli.
- The specific ion channels responsible for this K+ efflux during apoptosis have not been identified.
Purpose of the Study:
- To identify the molecular identity of K+ channels involved in apoptosis in cortical neurons.
- To investigate the role of Kv2.1 channels in neuronal apoptosis and their sufficiency in sensitizing non-neuronal cells to cell death.
Main Methods:
- Utilized dominant-negative Kv2.1 constructs to inhibit channel function in cortical neurons.
- Examined K+ currents and apoptosis levels in neurons treated with oxidants or staurosporine.
- Expressed wild-type Kv2.1 in Chinese hamster ovary (CHO) cells, which lack endogenous voltage-gated K+ channels.
Main Results:
- Dominant-negative Kv2.1 subunits abolished K+ current enhancement during apoptosis in neurons.
- Neurons lacking functional Kv2.1 channels were protected against oxidant- and staurosporine-induced apoptosis.
- Kv2.1 expression in CHO cells significantly increased their sensitivity to apoptosis-inducing agents.
Conclusions:
- Kv2.1-encoded K+ channels are necessary for the apoptotic signaling cascade in cultured mammalian cortical neurons.
- Kv2.1 channels are sufficient to confer increased susceptibility to apoptosis in non-excitable cells.