High K+ and IGF-1 Protect Cerebellar Granule Neurons Via Distinct Signaling Pathways

Jin Zhong, Jixian Deng, Su Huang, Xianlin Yang, Wei Hua Lee

Research output: Contribution to journalArticle

46 Scopus citations

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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)794-806
Number of pages13
JournalJournal of Neuroscience Research
Volume75
Issue number6
DOIs
StatePublished - Mar 15 2004

Keywords

  • Calcium
  • MAPK
  • Potassium
  • Survival

ASJC Scopus subject areas

  • Neuroscience(all)

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