Received for publication September 10, 2004.
Revised December 14, 2004.
Accepted for publication January 3, 2005.

Glycogen synthase kinase 3 activity mediates neuronal pentraxin 1 expression and cell death induced by potassium deprivation in cerebellar granule cells

Abstract

Expression of Neuronal Pentraxin 1 (NP1) is part of the apoptotic cell death program activated in mature cerebellar granule neurons when potassium concentrations drop below depolarizing levels. NP1 is a glycoprotein homologous to the pentraxins of the acute phase immune response and it is involved in both synaptogenesis and synaptic remodeling. However, how it participates in the process of apoptotic neuronal death remains unclear. We have studied whether the signaling pathways known to control neuronal cell death and survival influence NP1 expression. Both activation of the phosphatidylinositol 3-kinase/Akt (PI-3-K/AKT) pathway by Insulin-like growth factor I and pharmacological blockage of the stress activated c-jun N-terminal kinase (JNK) offer transitory neuroprotection from the cell death evoked by non-depolarizing concentrations of potassium. However, neither of these neuroprotective treatments prevent the overexpression of NP1 upon potassium depletion, indicating that non-depolarizing conditions activate additional cell death signaling pathways. Inhibiting the phosphorylation of the p38 mitogen activated protein kinase without modifying JNK, neither diminishes cell death nor inhibits NP1 overexpression in non-depolarizing conditions. In contrast, impairing the activity of Glycogen Synthase Kinase 3 (GSK3) completely blocks NP1 overexpression induced by potassium depletion and provides transient protection against cell death. Moreover, simultaneous pharmacological blockage of both JNK and GSK3 activities provides long-term protection against the cell death evoked by potassium depletion. These results show that both the JNK and GSK3 signaling pathways are the main routes by which potassium deprivation activates apoptotic cell death, and that NP1 overexpression is regulated by GSK3 activity independently of the PI-3-K/AKT or JNK pathways.

Key words: Jun Kinase, Apoptosis, Mechanisms of cell killing/apoptosis, Excitotoxicity, neurodegeneration

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