Regulation of the glutamate transporter EAAC1 by expression and activation of delta-opioid receptor.

Glutamate transporters play an essential role in regulating temporal and spatial glutamate concentration in the synaptic cleft. The excitatory amino acid carrier 1 (EAAC1) is a neuronal-specific transporter. Opioid receptors are found to modulate the glutamatergic system in brain, but the regulatory mechanism remains to be investigated. Here we report that the delta-opioid receptor (DOR) co-expressed with EAAC1 in Xenopus oocytes, but not the micro-opioid receptor, down-regulates EAAC1 function, and that [d-Pen(2,5)]-enkephalin stimulation of DOR can counteract the down-regulation of the EAAC1-mediated uptake. Results from co-immunoprecipitation and immunofluorescence microscopy in both oocytes and rat hippocampal neurons indicate co-localization and suggest direct interaction between DOR and EAAC1. The results suggest that DOR can reduce EAAC1 function by direct protein-protein interaction and that activation of DOR releases the inhibitory interaction. We suggest that this mechanism may be important for modulation of the glutamatergic system following opioid stimulation.