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High K+ and IGF-1 protect cerebellar granule neurons via distinct signaling pathways.
J Neurosci Res. 2004 Mar 15; 75(6):794-806.JN

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.

Authors+Show Affiliations

Departments of Pediatrics and Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

14994340

Citation

Zhong, Jin, et al. "High K+ and IGF-1 Protect Cerebellar Granule Neurons Via Distinct Signaling Pathways." Journal of Neuroscience Research, vol. 75, no. 6, 2004, pp. 794-806.
Zhong J, Deng J, Huang S, et al. High K+ and IGF-1 protect cerebellar granule neurons via distinct signaling pathways. J Neurosci Res. 2004;75(6):794-806.
Zhong, J., Deng, J., Huang, S., Yang, X., & Lee, W. H. (2004). High K+ and IGF-1 protect cerebellar granule neurons via distinct signaling pathways. Journal of Neuroscience Research, 75(6), 794-806.
Zhong J, et al. High K+ and IGF-1 Protect Cerebellar Granule Neurons Via Distinct Signaling Pathways. J Neurosci Res. 2004 Mar 15;75(6):794-806. PubMed PMID: 14994340.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - High K+ and IGF-1 protect cerebellar granule neurons via distinct signaling pathways. AU - Zhong,Jin, AU - Deng,Jixian, AU - Huang,Su, AU - Yang,Xianlin, AU - Lee,Wei-Hua, PY - 2004/3/3/pubmed PY - 2004/5/5/medline PY - 2004/3/3/entrez SP - 794 EP - 806 JF - Journal of neuroscience research JO - J Neurosci Res VL - 75 IS - 6 N2 - 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. SN - 0360-4012 UR - https://www.unboundmedicine.com/medline/citation/14994340/High_K+_and_IGF_1_protect_cerebellar_granule_neurons_via_distinct_signaling_pathways_ L2 - https://doi.org/10.1002/jnr.20024 DB - PRIME DP - Unbound Medicine ER -