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Involvement of Calpain/p35-p25/Cdk5/NMDAR Signaling Pathway in Glutamate- Induced Neurotoxicity in Cultured Rat Retinal Neurons.
- Source :
-
PLoS ONE . Aug2012, Vol. 7 Issue 8, Special section p1-12. 12p. - Publication Year :
- 2012
-
Abstract
- We investigated possible involvement of a calpain/p35-p25/cyclin-dependent kinase 5 (Cdk5) signaling pathway in modifying NMDA receptors (NMDARs) in glutamate-induced injury of cultured rat retinal neurons. Glutamate treatment decreased cell viability and induced cell apoptosis, which was accompanied by an increase in Cdk5 and p-Cdk5T15 protein levels. The Cdk5 inhibitor roscovitine rescued the cell viability and inhibited the cell apoptosis. In addition, the protein levels of both calpain 2 and calpain-specific alpha- spectrin breakdown products (SBDPs), which are both Ca2+ -dependent, were elevated in glutamate-induced cell injury. The protein levels of Cdk5, p- Cdk5T15, calpain 2 and SBDPs tended to decline with glutamate treatments of more than 9 h. Furthermore, the elevation of SBDPs was attenuated by either D-APV, a NMDAR antagonist, or CNQX, a non-NMDAR antagonist, but was hardly changed by the inhibitors of intracellular calcium stores dantrolene and xestospongin. Moreover, the Cdk5 co-activator p35 was significantly up- regulated, whereas its cleaved product p25 expression showed a transient increase. Glutamate treatment for less than 9 h also considerably enhanced the ratio of the Cdk5-phosphorylated NMDAR subunit NR2A at Ser1232 site (p- NR2AS1232) and NR2A (p-NR2AS1232/NR2A), and caused a translocation of p-NR2AS1232 from the cytosol to the plasma membrane. The enhanced p-NR2AS1232 was inhibited by roscovitine, but augmented by over-expression of Cdk5. Calcium imaging experiments further showed that intracellular Ca2+ concentrations ([Ca2+]I) of retinal cells were steadily increased following glutamate treatments of 2 h, 6 h and 9 h. All these results suggest that the activation of the calpain/p35- p25/Cdk5 signaling pathway may contribute to glutamate neurotoxicity in the retina by up-regulating p-NR2AS1232 expression. [ABSTRACT FROM AUTHOR]
- Subjects :
- *CALPAIN
*KINASES
*GLUTAMIC acid
*NEURONS
*RETINA
*PROTEINS
*APOPTOSIS
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 7
- Issue :
- 8
- Database :
- Academic Search Index
- Journal :
- PLoS ONE
- Publication Type :
- Academic Journal
- Accession number :
- 80434154
- Full Text :
- https://doi.org/10.1371/journal.pone.0042318