@Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways (2002)

2022-05-01: reference:

@Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways (2002) #

Their actions are opposite: while synaptic NMDAR activity induces that of CREB, eNMDAR the pathway and therefore BDNF etc.

• Synaptic NMDA receptor activation was found to be neuroprotective.

• Stimulation of NMDA receptors by synaptic activity robustly activated CREB and CREB target gene expression, to about the same extent as L-type calcium channels.

  • Blocking L-type calcium channels with nifedipine did not reduce CRE-reporter gene expression after action potential bursts, though it did inhibit the response triggered by KClinduced membrane depolarization
    • Might be relevant, idk.
  • This whole deal can be replicated with Bicuculline treatment, which does not cause activation of extrasynaptic NMDAR.

• Glutamate treatment only poorly affected CREB and did not induce BDNF expression or TrkB phosphorylation.

  • The failure of glutamate to activate CREB function was due to specific coupling of eNMDAR receptors to a CREB shut-off pathway that antagonized the CREB-promoting activity of synaptic NMDA receptors.

• eNMDAR are composed predominantly of NR1x and NR2B. “Ifenprodil, a selective but incomplete inhibitor of NR2B may therefore preferentially inibit extrasynaptic NMDAR.”: for eNMDAR and synaptic respectively: 71% instead of 53% blocking of calcium transients for. Completely blocked CREB dephosphorylation/‘decay’. Wtf?

• NMDA receptor-mediated excitotoxicity depends on the coactivation of synaptic and extrasynaptic receptors (2013)

  • 

Basically, they don’t really take a stab at how their signaling cascades might differ as it relates to CREB. For now it seems to be pretty much unknown.