Disruption of KV2.1 somato-dendritic clusters prevents the apoptogenic increase of potassium currents

Abstract As the predominant mediator of the delayed rectifier current, K V 2.1 is an important regulator of neuronal excitability. K V 2.1, however, also plays a well-established role in apoptotic cell death. Apoptogenic stimuli induce syntaxin-dependent trafficking of K V 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 K V 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 K V 2.1. However, it is unknown whether K V 2.1 somato-dendritic clusters are required for apoptogenic trafficking of K V 2.1. By overexpression of a protein derived from the C-terminus of the cognate channel K V 2.2 (K V 2.2CT), we induced calcineurin-independent disruption of K V 2.1 somato-dendritic clusters in rat cortical neurons, without altering the electrophysiological properties of the channel. We observed that K V 2.2CT-expressing neurons are less susceptible to oxidative stress-induced cell death. Critically, expression of K V 2.2CT effectively blocked the increased current density of the delayed rectifier current associated with oxidative injury, supporting a vital role of K V 2.1-somato-dendritic clusters in apoptogenic increases in K V 2.1-mediated currents.