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Neuritin Up-regulates Kv4.2 α -Subunit of Potassium Channel Expression and Affects Neuronal Excitability by Regulating the Calcium-Calcineurin-NFATc4 Signaling Pathway *

View Article: PubMed Central - PubMed

ABSTRACT

Neuritin is an important neurotrophin that regulates neural development, synaptic plasticity, and neuronal survival. Elucidating the downstream molecular signaling is important for potential therapeutic applications of neuritin in neuronal dysfunctions. We previously showed that neuritin up-regulates transient potassium outward current (IA) subunit Kv4.2 expression and increases IA densities, in part by activating the insulin receptor signaling pathway. Molecular mechanisms of neuritin-induced Kv4.2 expression remain elusive. Here, we report that the Ca2+/calcineurin (CaN)/nuclear factor of activated T-cells (NFAT) c4 axis is required for neuritin-induced Kv4.2 transcriptional expression and potentiation of IA densities in cerebellum granule neurons. We found that neuritin elevates intracellular Ca2+ and increases Kv4.2 expression and IA densities; this effect was sensitive to CaN inhibition and was eliminated in Nfatc4−/− mice but not in Nfatc2−/− mice. Stimulation with neuritin significantly increased nuclear accumulation of NFATc4 in cerebellum granule cells and HeLa cells, which expressed IR. Furthermore, NFATc4 was recruited to the Kv4.2 gene promoter loci detected by luciferase reporter and chromatin immunoprecipitation assays. More importantly, data obtained from cortical neurons following adeno-associated virus-mediated overexpression of neuritin indicated that reduced neuronal excitability and increased formation of dendritic spines were abrogated in the Nfatc4−/− mice. Together, these data demonstrate an indispensable role for the CaN/NFATc4 signaling pathway in neuritin-regulated neuronal functions.

No MeSH data available.


Schematic illustration depicting Ca2+/CaN-dependent NFATc4 activity on the modulation of neuritin-induced Kv4.2 expression and the subsequent increase in IA channel density.
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Figure 8: Schematic illustration depicting Ca2+/CaN-dependent NFATc4 activity on the modulation of neuritin-induced Kv4.2 expression and the subsequent increase in IA channel density.

Mentions: We previously reported that neuritin-up-regulated Kv4.2 expression was associated with the activation of both MEK-ERK and Akt-mTOR pathways in rat CGNs via the IR (5). A recent observation by Ulrich et al. (19) demonstrated that inhibition of p38 or mTOR kinases had no significant effect on translocation of NFATc4 in dorsal root ganglion neurons, which may be due to the fact that the Akt-mTOR pathway is more specific to translational processes during protein synthesis (43). This study further suggested that there was cross-talk between CaN and ERK in the CaN-NFATc4 pathway even though it was the Akt-mTOR pathway that was involved in neuritin-induced Kv4.2 expression (5). Our data are consistent with the observation of Ulrich et al. (19) that inhibition of p38 or mTOR kinases had no significant effect on translocation of NFATc4 in dorsal root ganglion neurons. Studies by Yang et al. (44) and Chandrasekar et al. (45) have shown that activation of ERK resulted in phosphorylation of Ser676 in NFATc4, which led to greater DNA binding of NFATc4 and provides an additional mechanism for the modulation of NFATc4 transcriptional activity. Thus, it is possible that neuritin activates the CaM-CaN pathway, which dephosphorylates NFATc4 at Ser168 and Ser170 and facilitates NFATc4 translocation into the nucleus. Meanwhile, neuritin also activates the Ras/Raf/ERK pathway, which phosphorylates NFATc4 at Ser676 and increases the DNA binding of NFATc4. These two signal pathways may thus work together to provide optimal conditions for NFATc4 to modulate transcription of the Kv4.2 gene. Further research will be needed to establish the existence of cross-talk between CaN and ERK. Fig. 8 is proposed as a model depicting the mechanisms likely involved in the transcriptional modulation of Kv4.2 expression by the CaN/NFATc4 signaling pathway in cerebellar GCs.


Neuritin Up-regulates Kv4.2 α -Subunit of Potassium Channel Expression and Affects Neuronal Excitability by Regulating the Calcium-Calcineurin-NFATc4 Signaling Pathway *
Schematic illustration depicting Ca2+/CaN-dependent NFATc4 activity on the modulation of neuritin-induced Kv4.2 expression and the subsequent increase in IA channel density.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5016134&req=5

Figure 8: Schematic illustration depicting Ca2+/CaN-dependent NFATc4 activity on the modulation of neuritin-induced Kv4.2 expression and the subsequent increase in IA channel density.
Mentions: We previously reported that neuritin-up-regulated Kv4.2 expression was associated with the activation of both MEK-ERK and Akt-mTOR pathways in rat CGNs via the IR (5). A recent observation by Ulrich et al. (19) demonstrated that inhibition of p38 or mTOR kinases had no significant effect on translocation of NFATc4 in dorsal root ganglion neurons, which may be due to the fact that the Akt-mTOR pathway is more specific to translational processes during protein synthesis (43). This study further suggested that there was cross-talk between CaN and ERK in the CaN-NFATc4 pathway even though it was the Akt-mTOR pathway that was involved in neuritin-induced Kv4.2 expression (5). Our data are consistent with the observation of Ulrich et al. (19) that inhibition of p38 or mTOR kinases had no significant effect on translocation of NFATc4 in dorsal root ganglion neurons. Studies by Yang et al. (44) and Chandrasekar et al. (45) have shown that activation of ERK resulted in phosphorylation of Ser676 in NFATc4, which led to greater DNA binding of NFATc4 and provides an additional mechanism for the modulation of NFATc4 transcriptional activity. Thus, it is possible that neuritin activates the CaM-CaN pathway, which dephosphorylates NFATc4 at Ser168 and Ser170 and facilitates NFATc4 translocation into the nucleus. Meanwhile, neuritin also activates the Ras/Raf/ERK pathway, which phosphorylates NFATc4 at Ser676 and increases the DNA binding of NFATc4. These two signal pathways may thus work together to provide optimal conditions for NFATc4 to modulate transcription of the Kv4.2 gene. Further research will be needed to establish the existence of cross-talk between CaN and ERK. Fig. 8 is proposed as a model depicting the mechanisms likely involved in the transcriptional modulation of Kv4.2 expression by the CaN/NFATc4 signaling pathway in cerebellar GCs.

View Article: PubMed Central - PubMed

ABSTRACT

Neuritin is an important neurotrophin that regulates neural development, synaptic plasticity, and neuronal survival. Elucidating the downstream molecular signaling is important for potential therapeutic applications of neuritin in neuronal dysfunctions. We previously showed that neuritin up-regulates transient potassium outward current (IA) subunit Kv4.2 expression and increases IA densities, in part by activating the insulin receptor signaling pathway. Molecular mechanisms of neuritin-induced Kv4.2 expression remain elusive. Here, we report that the Ca2+/calcineurin (CaN)/nuclear factor of activated T-cells (NFAT) c4 axis is required for neuritin-induced Kv4.2 transcriptional expression and potentiation of IA densities in cerebellum granule neurons. We found that neuritin elevates intracellular Ca2+ and increases Kv4.2 expression and IA densities; this effect was sensitive to CaN inhibition and was eliminated in Nfatc4−/− mice but not in Nfatc2−/− mice. Stimulation with neuritin significantly increased nuclear accumulation of NFATc4 in cerebellum granule cells and HeLa cells, which expressed IR. Furthermore, NFATc4 was recruited to the Kv4.2 gene promoter loci detected by luciferase reporter and chromatin immunoprecipitation assays. More importantly, data obtained from cortical neurons following adeno-associated virus-mediated overexpression of neuritin indicated that reduced neuronal excitability and increased formation of dendritic spines were abrogated in the Nfatc4−/− mice. Together, these data demonstrate an indispensable role for the CaN/NFATc4 signaling pathway in neuritin-regulated neuronal functions.

No MeSH data available.