Functional Interaction between Adenosine A and mGlu Receptors Mediates STEP Phosphatase Activation and Promotes STEP/mGluR Binding in Mouse Hippocampus and Neuroblastoma Cell Line.

(1) Background: Recently, we found that adenosine A receptor (AR) stimulation results in an increase in STEP phosphatase activity. In order to delve into the mechanism through which AR stimulation induced STEP activation, we investigated the involvement of mGluR since it is well documented that AR and mGluR physically and functionally interact in several brain areas. (2) Methods: In a neuroblastoma cell line (SH-SY5Y) and in mouse hippocampal slices, we evaluated the enzymatic activity of STEP by using a para-nitrophenyl phosphate colorimetric assay. A co-immunoprecipitation assay and a Western blot analysis were used to evaluate STEP/mGluR binding. (3) Results: We found that the AR-dependent activation of STEP was mediated by the mGluR. Indeed, the AR agonist CGS 21680 significantly increased STEP activity, and this effect was prevented not only by the AR antagonist ZM 241385, as expected, but also by the mGluR antagonist MPEP. In addition, we found that mGluR agonist DHPG-induced STEP activation was reversed not only by the mGluR antagonist MPEP but also by ZM 241385. Finally, via co-immunoprecipitation experiments, we found that mGluR and STEP physically interact when both receptors are activated (4) Conclusions: These results demonstrated a close functional interaction between mGlu and A receptors in the modulation of STEP activity.