Scaffolding of Fyn Kinase to the NMDA Receptor Determines Brain Region Sensitivity to Ethanol

Abstract

Alcohol (ethanol) abuse is a major societal problem. Although ethanol is a structurally simple, diffusible molecule, its sites of action are surprisingly selective, and the molecular mechanisms underlying specificity in ethanol actions are not understood. The NMDA receptor channel is one of the main targets for ethanol in the brain. We report here that the brain region-specific compartmentalization of Fyn kinase determines NMDA receptor sensitivity to ethanol. We demonstrate that, in the hippocampus but not in the cerebral cortex, Fyn is targeted to the NR2B subunit of the NMDA receptor by the scaffolding protein RACK1. During acute exposure to ethanol, RACK1 is dissociated from the complex, thereby facilitating Fyn-mediated phosphorylation of NR2B, which enhances channel activity, counteracting the inhibitory actions of ethanol. In this way, the selective scaffolding can account for the ethanol-induced acute tolerance of NMDA receptor activity that is detected in the hippocampus but not in the cerebral cortex. The phosphorylation-dependent, region-specific activities of ethanol on the NMDA receptor provide a compelling molecular explanation that accounts for the selective activities of ethanol and may have important implications for elucidating pathways leading to alcohol addiction.

Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase

“…A similar increase of NMDAR currents after ethanol treatment had been previously observed in the hippocampus (33) and in dorsal striatum (34). It has been reported that STEP inactivates Fyn (35), a SFK that phosphorylates tyrosine residues on the NMDAR and enhances its function (12).…”

“…All experiments with kinase or phosphatase inhibitors are fraught with difficulties in interpretation. Nevertheless, these data suggest the possibility that ethanol's potentiating effects on the NMDAR might be regulated by the SFK Fyn, as has been suggested previously (28,33). However, the potentiating effect of ethanol that we have seen in the STEP KO animals is not likely to be caused by an increase in NMDAR phosphorylation, as ethanol produces no increase, but rather a modest decrease, in NMDAR phosphorylation in STEP KO animals.…”

Ethanol Reduces Neuronal Excitability of Lateral Orbitofrontal Cortex Neurons Via a Glycine Receptor Dependent Mechanism

“…However, unlike NMDA currents in those reports that were recorded from central amygdala and BNST, NMDA EPSCs in lOFC neurons and hippocampus (Suvarna et al, 2005) are significantly inhibited by EtOH even in the presence of Ro-25-6981 that by itself reduces the amplitude of NMDA evoked responses. These findings point out that while subunit composition may influence the overall EtOH sensitivity of NMDA receptors in some brain regions, other factors such as those related to receptor phosphorylation and trafficking (Alvestad et al, 2003;Wu et al, 2011;Yaka et al, 2003) may contribute to EtOH's action on neuronal NMDA receptors.…”

Adaptive plasticity of NMDA receptors and dendritic spines: Implications for enhanced vulnerability of the adolescent brain to alcohol addiction

“…In addition, the selective targeting of NMDA receptors to the synapse in response to prolonged ethanol exposure appears to be distinct from adaptations involved in acute tolerance to ethanol. In mice, acute ethanol exposure induces the rapid tyrosine phosphorylation of NR2B in the hippocampus (Yaka, et al, 2003a). This phosphorylation is most likely mediated via activation of Fyn tyrosine kinase since enhanced phosphorylation was not observed in Fyn-deficient mice (Miyakawa, et al, 1997).…”