The hippocampal N-methyl-D-aspartate receptor (NMDAR) activity plays important roles in cognition and is a major substrate for ethanol-induced memory dysfunction. This receptor is a glutamate-gated ion channel, which composes of NR1 and NR2 subunits in various brain areas. While homomeric NR1 subunits form an active ion channel that conducts Na+ and Ca2+ currents, the incorporation of NR2 subunits allows this channel to be modulated by the Src family of kinases, phosphatases, and by simple molecules such as ethanol. Recently, we found that acute ethanol inhibits the NMDAR activity via STriatal Enriched protein tyrosine Phosphatase (STEP)-regulated mechanisms. The genetic deletion of the active form of STEP, STEP61, leads to marked attenuation of acute ethanol inhibition of NMDAR currents. Also, STEP61 negatively regulates Fyn and p38 mitogen-activated protein kinase (p38 MAPK), and these proteins are members of the NMDAR super molecular complex.
Here, we demonstrate, using whole-cell electrophysiological recording, Western blot analysis and pharmacological manipulations, that neurons exposed to a 3-hour, 45 mM ethanol treatment develop an adaptive attenuation of acute ethanol inhibition on NMDAR currents in brain slices.
Our results suggest that this adaptation of NMDAR responses is associated with 1) a partial inactivation of STEP61, 2) an activation of p38 MAPK, and 3) a requirement for NR2B activity.
Together, these data indicate that altered STEP61 and p38 MAPK signaling contribute to the modulation of ethanol inhibition of NMDARs in brain neurons.
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