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

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.

Bone Morphogenetic Protein-6 Promotes Cerebellar Granule Neurons Survival by Activation of the MEK/ERK/CREB Pathway

“…CREB activation has been implicated in synaptic plasticity, learning, and memory and cell survival (Lonze and Ginty, 2002;Carlezon et al, 2005). Moreover, CREB activation has been reported to be a necessary step in CGC survival and differentiation during the postnatal development (Monti et al, 2002;Zhong et al, 2004). In this context, we have observed that BMP-6, but not BMP-7, activates CREB via the MEK/ERK pathway and this activation is required for the decrease in caspase-3 activity.…”

“…CREB has a key role on the survival of CGCs (Bonni et al, 1999;Monti et al, 2002;Yabe et al, 2002;Zhong et al, 2004;Jia et al, 2007). It is well known that CREB is phosphorylated and activated by the MEK/ERK pathway.…”

Characterization of C3a and C5a Receptors in Rat Cerebellar Granule Neurons during Maturation

“…In particular, inhibition of MEK (mitogen-activated protein kinase kinase) phosphorylation by PD98059 prevented the inhibition of caspase-3 by C5a (64). The mitogen-activated protein kinase pathway has been reported to be involved in the control of granule cells apoptosis (65) and differentiation, so we can speculate that this cascade can be another alternative for the antiapoptotic effect of C5a. Mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways are currently being investigated.…”

Drug target identification at the crossroad of neuronal apoptosis and survival

“…Although the survival effects of these neurotrophic factors are mediated by different receptors and intracellular second messengers [31,32], they are propagated by common transcriptional cascades and show striking similarities [33] (Figures 2 and 3). Indeed, not only a majority of differentially expressed genes, defined as 'survival related genes' (SRGs), are common to Igf1 and Pacap (Figure 2), but also the Pearson correlation coefficient between Igf1 and Pacap for all SRGs is 0.97 [33].…”