Cyclin E1 Regulates Kv2.1 Channel Phosphorylation and Localization in Neuronal Ischemia

Abstract

Kv2.1 is a major delayed rectifying Kϩ channel normally localized to highly phosphorylated somatodendritic clusters in neurons. Excitatory stimuli induce calcineurin-dependent dephosphorylation and dispersal of Kv2.1 clusters, with a concomitant hyperpolarizing shift in the channel's activation kinetics. We showed previously that sublethal ischemia, which renders neurons transiently resistant to excitotoxic cell death, can also induce Zn 2ϩ -dependent changes in Kv2.1 localization and activation kinetics, suggesting that activitydependent modifications of Kv2.1 may contribute to cellular adaptive responses to injury. Recently, cyclin-dependent kinase 5 (Cdk5) was shown to phosphorylate Kv2.1, with pharmacological Cdk5 inhibition being sufficient to decluster channels. In another study, cyclin E1 was found to restrict neuronal Cdk5 kinase activity. We show here that cyclin E1 regulates Kv2.1 cellular localization via inhibition of Cdk5 activity. Expression of cyclin E1 in human embryonic kidney cells prevents Cdk5-mediated phosphorylation of Kv2.1, and cyclin E1 overexpression in rat cortical neurons triggers dispersal of Kv2.1 channel clusters. Sublethal ischemia in neurons induces calcineurindependent upregulation of cyclin E1 protein expression and cyclin E1-dependent Kv2.1 channel declustering. Importantly, overexpression of cyclin E1 in neurons is sufficient to reduce excitotoxic cell death. These results support a novel role for neuronal cyclin E1 in regulating the phosphorylation status and localization of Kv2.1 channels, a likely component of signaling cascades leading to ischemic preconditioning.

Physiological roles of Kv2 channels in entorhinal cortex layer II stellate cells revealed by Guangxitoxin‐1E

“…) and cyclin E1 during ischaemia (Shah et al . ). In CA1 pyramidal neurons, modulation of the Kv2 channels by glutamate receptors tends to enhance the impact of the Kv2–mediated current ( I K ) by inducing a hyperpolarizing shift in its activation range (Misonou et al .…”

Organizing neuronal ER-PM junctions is a conserved nonconducting function of Kv2 plasma membrane ion channels

“…We note that the clustering of Kv2.1 is conditional in many if not all of these cell backgrounds, such that it occurs in M-phase but not interphase COS-1 cells (47), polarized MDCK cells in confluent epithelial monolayers but not in nonpolarized MDCK cells in low density culture (35), and in PC12 cells before but not after differentiation with nerve growth factor (102). Moreover, in neurons and HEK293 cells, changes in protein kinase (54, 99) and protein phosphatase (39, 52, 53, 80, 103, 104) activity leads to changes in Kv2.1 phosphorylation state and clustering, and presumably its association with ER-PM junctions. As such, the mechanism whereby Kv2.1 organizes ER-PM junctions may involve regulation via dynamic changes in phosphorylation state, including in critical serine residues within the PRC domain itself (37, 47).…”

Transcriptional Regulation of the Sodium-activated Potassium Channel SLICK (KCNT2) Promoter by Nuclear Factor-κB

“…Indeed, SK2 channel openers were shown to reduce neuronal cell death during ischemia (29). Potassium channels are important for countering the ischemia-induced excitotoxicity in neurons (30,31). During ischemic excitotoxicity, neurons experience elevations in intracellular calcium, sodium, and chloride, causing changes in neuronal cell volume and eventual death.…”