Activation of GABA receptors attenuates neuronal apoptosis through inhibiting the tyrosine phosphorylation of NR2A by Src after cerebral ischemia and reperfusion

Tyrosine Phosphorylation of the NMDA Receptor Following Cerebral Ischaemia

“…Notably, ischaemia-mediated tyrosine phosphorylation was found to increase, by approximately twofold, the association of Src and Fyn with both GluN2A and GluN2B during reperfusion [226]. In agreement, a number of subsequent studies also observed greater association of SFKs with GluN2A during the first six hours following global ischaemia in adult rats [97,98,135,248,273]. As well, hypoxia-ischaemia applied to neonatal rats [103] and OGD of cultured neurones prepared from late-stage embryonic animals [268] also lead to greater co-immunoprecipitation of SFKs and the GluN2A subunit.…”

“…Within several hours of reperfusion following global ischaemia, a general increase in the level of tyrosine phosphorylation at hippocampal Src was observed [135,136]; as well, a specific increase in Y416 phosphorylation was found within the whole hippocampus [38,79,248,258,273], and the CA1 [130,264,273] and CA3-dentate gyrus [79] regions. The level of phosphorylated Y416 was also found to be increased in both synaptosomes [160] and post-synaptic densities [16,35,160] prepared from the rodent forebrain region after the return of blood supply to the insulted area.…”

“…Within whole hippocampal homogenates, the level of Src was not found to change during a six hour period of reperfusion following either global ischaemia in adult animals [273], or hypoxia-ischaemia in pre-weanling animals [103]. In contrast, during the same length of time after global ischaemia the level of both Src and Fyn proteins were observed to experience about a twofold increase within the post-synaptic density [16,34,226].…”

GABABReceptor Activation Protects Neurons from Apoptosis via IGF-1 Receptor Transactivation

“…G␣ i/o subunits modulate the level of cAMP by regulating adenylate cyclase activities at postsynaptic sites, and inhibition of neuronal excitability (Simonds, 1999;Billinton et al, 2001). Interestingly, recent studies suggest that in addition to a role in neuronal excitability and plasticity, GABA B receptor may promote neuronal survival under conditions of metabolic stress or after ischemia (Dave et al, 2005;Kuramoto et al, 2007;Zhang et al, 2007). Accumulating evidences have shown that GABA B receptor plays an important role in anxiety and depression related disorders while the different classes of antidepressants and mood stabilizers that have been shown to prevent cell death (Cryan and Kaupmann, 2005;McKernan et al, 2009).…”

Glutamate Transporters and the Excitotoxic Path to Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis

“…However, some considerations should be pointed out regarding this study: (a) the analysis of the neuronal loss was only limited to 24 h after infusion of PDC; (b) although no increased neuronal loss was detected, the study does not indicate whether the neurons exposed to high concentrations of glutamate were indeed starting to become dysfunctional and still progress to dead motor neurons if observed over a longer temporal scale; and (c) extracellular GABA levels were not reported. An increase in GABA release, which could have been induced concurrent with the PDC-mediated increase in extracellular glutamate, would considerably dampen the excitation of neurons and effectively protect them from the excitotoxic insult produced by the blockade of glutamate transporters (28,77,158).…”