Neuroprotection associated with alternative splicing of NMDA receptors in rat cortical neurons
Version of Record online: 30 JAN 2009
2006 British Pharmacological Society
British Journal of Pharmacology
Volume 147, Issue 6, pages 622–633, March 2006
How to Cite
Jaekel, B., Mühlberg, K., Garcia de Arriba, S., Reichenbach, A., Verdaguer, E., Pallas, M., Camins, A., Nörenberg, W. and Allgaier, C. (2006), Neuroprotection associated with alternative splicing of NMDA receptors in rat cortical neurons. British Journal of Pharmacology, 147: 622–633. doi: 10.1038/sj.bjp.0706471
- Issue online: 30 JAN 2009
- Version of Record online: 30 JAN 2009
- (Received July 25, 2005, Revised October 3, 2005, Accepted October 17, 2005)
- NMDA receptors;
- receptor adaptation;
- cultured cortical neurons
Exposure of cultured cortical neurons to elevated extracellular K+ concentrations (25 mM) induces membrane depolarization and an increase in action-potential firing.
Long-term high K+ treatment was associated with an increased neuronal cell death.
In surviving neurons, multiple changes occurred in the proportion of individual NMDA receptor subunit 1 (NR1) splice variant mRNA expression, whereas the overall expression of NR1, NR2A and NR2B transcripts remained unaffected. The high K+-induced changes in NR1 splice variant expression were virtually abolished upon a concurrent administration of tetrodotoxin (TTX; 3 μM).
In voltage-clamp recordings performed on neurons resistant to high K+ treatment, inward currents induced by NMDA (1–1000 μM) were reduced.
In K+-resistant cells, the activity of calpain but not of caspase-3 was diminished compared with controls kept in regular medium.
NR function as well as calpain activity was not affected in cultures concomitantly treated with high K+ and either TTX or a NR antagonist (CGS19755 (selfotel) or memantine).
In conclusion, the present data indicate adaptive changes in NR1 splice variant expression and a decrease in NR function upon a sustained increase in neurotransmission. Accordingly, alternative splicing could be an endogenous mechanism to counteract cellular damage due to overactivation of excitatory NRs and may be associated with an impairment of necrotic mechanisms.
British Journal of Pharmacology (2006) 147, 622–633. doi:10.1038/sj.bjp.0706471