Related Experiment Videos
Lithium blocks the PKB and GSK3 dephosphorylation induced by ceramide through protein phosphatase-2A
Alfonso Mora1, Guadalupe Sabio, Ana María Risco
1Departamento de Bioquímica y Biología Molecular, Facultad de Veterinaria, Universidad de Extremadura, Avenida Universidad s/n, 10071 Cáceres, Spain. almoraco@unex.es
Abstract:
The biochemical mechanism of apoptosis induced by ceramide remains still unclear, although it has been reported that dephosphorylation of PKB at Ser-473 may be a key event. In this article, we show that C(2)-ceramide (N-acetyl-sphingosine) induces the dephosphorylation of both protein kinase B (PKB) and glycogen synthase kinase-3 (GSK3) in cerebellar granule cells (CGC). We also show that lithium protects against the apoptosis induced by C(2)-ceramide by blocking the dephosphorylation of both kinases. Since lithium inhibits in vivo the observed protein phosphatase-2A (PP2A) activation induced by ceramide, we hypothesise that the neuroprotective action of lithium may be due to the inhibition of the PP2A activation by apoptotic stimuli.
Insights
Ceramide triggers apoptosis by dephosphorylating protein kinase B (PKB) and glycogen synthase kinase-3 (GSK3). Lithium prevents this apoptosis by inhibiting protein phosphatase-2A (PP2A) activation, suggesting a neuroprotective role.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- The precise biochemical pathways driving ceramide-induced apoptosis are not fully understood.
- Dephosphorylation of protein kinase B (PKB) at Ser-473 is a potential key event in this process.
Purpose of the Study:
- To investigate the effects of C(2)-ceramide on PKB and GSK3 dephosphorylation in cerebellar granule cells (CGC).
- To determine if lithium can protect against ceramide-induced apoptosis and elucidate its mechanism of action.
Main Methods:
- Treatment of CGC with C(2)-ceramide and lithium.
- Analysis of PKB and GSK3 phosphorylation status.
- Assessment of apoptosis induction and inhibition.
- In vivo investigation of PP2A activation.
Main Results:
- C(2)-ceramide induced dephosphorylation of both PKB and GSK3 in CGC.
- Lithium treatment blocked C(2)-ceramide-induced dephosphorylation of PKB and GSK3, thereby protecting against apoptosis.
- Lithium was found to inhibit ceramide-induced PP2A activation in vivo.
Conclusions:
- Ceramide-induced apoptosis in CGC involves the dephosphorylation of PKB and GSK3.
- Lithium exhibits neuroprotective effects against ceramide-induced apoptosis.
- The neuroprotective action of lithium may stem from its ability to inhibit PP2A activation by apoptotic stimuli.