RGD Reference Report - Scaffolding of Fyn kinase to the NMDA receptor determines brain region sensitivity to ethanol. - Rat Genome Database

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Scaffolding of Fyn kinase to the NMDA receptor determines brain region sensitivity to ethanol.

Authors: Yaka, R  Phamluong, K  Ron, D 
Citation: Yaka R, etal., J Neurosci 2003 May 1;23(9):3623-32.
RGD ID: 1358550
Pubmed: PMID:12736333   (View Abstract at PubMed)
PMCID: PMC1262669   (View Article at PubMed Central)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
ionotropic glutamate receptor signaling pathway  TAS 1358550 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Fyn  (FYN proto-oncogene, Src family tyrosine kinase)


Additional Information