Disruption of K V 2.1 somato-dendritic clusters prevents the apoptogenic increase of potassium currents.

As the predominant mediator of the delayed rectifier current, KV 2.1 is an important regulator of neuronal excitability. KV 2.1, however, also plays a well-established role in apoptotic cell death. Apoptogenic stimuli induce syntaxin-dependent trafficking of KV 2.1, resulting in an augmented delayed rectifier current that acts as a conduit for K+ efflux required for pro-apoptotic protease/nuclease activation. Recent evidence suggests that KV 2.1 somato-dendritic clusters regulate the formation of endoplasmic reticulum-plasma membrane junctions that function as scaffolding sites for plasma membrane trafficking of ion channels, including KV 2.1. However, it is unknown whether KV 2.1 somato-dendritic clusters are required for apoptogenic trafficking of KV 2.1. By overexpression of a protein derived from the C-terminus of the cognate channel KV 2.2 (KV 2.2CT), we induced calcineurin-independent disruption of KV 2.1 somato-dendritic clusters in rat cortical neurons, without altering the electrophysiological properties of the channel. We observed that KV 2.2CT-expressing neurons are less susceptible to oxidative stress-induced cell death. Critically, expression of KV 2.2CT effectively blocked the increased current density of the delayed rectifier current associated with oxidative injury, supporting a vital role of KV 2.1-somato-dendritic clusters in apoptogenic increases in KV 2.1-mediated currents.