High K⁺ and IGF‐1 protect cerebellar granule neurons via distinct signaling pathways

• Jin Zhong

• Jixian Deng

• Su Huang

• Xianlin Yang

• Wei‐Hua Lee

Abstract

In culture, cerebellar granule neurons die of apoptosis in serum‐free media containing a physiologic level of K + but survive in a depolarizing concentration of K + or when insulin‐like growth factor 1 (IGF‐1) is added. Both Akt/PKB activation and caspase‐3 inhibition were implicated as the underlying neuroprotective mechanisms. The duration of high K + , however, induced survival effects that outlasted its transient activation of Akt, and granule neurons derived from caspase‐3 knockout mice died to the same extent as did those from wild‐type mice, suggesting that additional mechanisms are involved. To delineate these survival mechanisms, we compared the activities of two major survival pathways after high K + ‐induced depolarization or IGF‐1 stimulation. Although IGF‐1 promoted neuronal survival by activating its tyrosine kinase receptor, high K + depolarization provided the same effect by increasing the Ca 2+ influx through the L Ca 2+ channel. Moreover, high K + ‐induced depolarization resulted in sustained activation of MAP kinase, whereas IGF‐1 activated Akt in 4 hr. Inhibition of MEK (MAP kinase kinase) by either PD98059 or UO126 abolished the protective effect of high K + ‐induced depolarization, but not that of IGF‐1, suggesting that activation of the MAP kinase pathway is necessary for high K + neuroprotective effects. We demonstrated also that high K + ‐induced depolarization, but not IGF‐1, increased phosphorylation of cAMP‐response element‐binding protein (CREB) and protein synthesis, both of which can be blocked by UO126. Overall, our findings suggested that high K + ‐induced depolarization, unlike IGF‐1, promoted neuronal survival via activating MAP kinase, possibly by increasing CREB‐dependent transcriptional activation of specific proteins that promote neuronal survival. © 2004 Wiley‐Liss, Inc.

Journal

• Journal of Neuroscience Research

  Journal of Neuroscience Research 75 (6), 794-806, 2004-02-25

  Wiley

Keywords

• Cellular and Molecular Neuroscience

Details

• CRID: 1361418521222723200
• NII Article ID: 30001890216
• DOI: 10.1002/jnr.20024
• ISSN: 10974547
• ISSN: 03604012
• Web Site: https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fjnr.20024
• Web Site: https://onlinelibrary.wiley.com/doi/pdf/10.1002/jnr.20024
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