Molecular Integration in Adenosine Heteroreceptor Complexes Through Allosteric and De-Phosphorylation (STEP) Mechanisms and its Role in Brain Disease

Borroto‐Escuela, Dasiel O.; Ferraro, Luca

doi:10.3389/fphar.2021.781381

Cited by 3 publications

(1 citation statement)

References 35 publications

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“…Given that the regulation of STEP has been implicated in the pathophysiology of a number of neurological and neuropsychiatric disorders [ 12 ], the interaction between A 2A R and mGlu 5 R in the modulation of STEP activity appears to be particularly interesting since it could have a role in brain diseases [ 33 ] and could be involved in the therapeutic effects of A 2A R and mGlu 5 R antagonists. Indeed, both A 2A R and mGlu 5 R antagonists have been demonstrated to be effective in animal models of Alzheimer’s disease [ 11 , 34 , 35 , 36 ] and of fragile X syndrome [ 37 , 38 , 39 , 40 ], in which increases in the expression and activity of STEP have been demonstrated [ 12 , 37 , 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

Functional Interaction between Adenosine A2A and mGlu5 Receptors Mediates STEP Phosphatase Activation and Promotes STEP/mGlu5R Binding in Mouse Hippocampus and Neuroblastoma Cell Line

Mallozzi,

Pepponi,

Gaddini

et al. 2023

Biomolecules

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(1) Background: Recently, we found that adenosine A2A receptor (A2AR) stimulation results in an increase in STEP phosphatase activity. In order to delve into the mechanism through which A2AR stimulation induced STEP activation, we investigated the involvement of mGlu5R since it is well documented that A2AR and mGlu5R 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/mGlu5R binding. (3) Results: We found that the A2AR-dependent activation of STEP was mediated by the mGlu5R. Indeed, the A2AR agonist CGS 21680 significantly increased STEP activity, and this effect was prevented not only by the A2AR antagonist ZM 241385, as expected, but also by the mGlu5R antagonist MPEP. In addition, we found that mGlu5R agonist DHPG-induced STEP activation was reversed not only by the mGlu5R antagonist MPEP but also by ZM 241385. Finally, via co-immunoprecipitation experiments, we found that mGlu5R and STEP physically interact when both receptors are activated (4) Conclusions: These results demonstrated a close functional interaction between mGlu5 and A2A receptors in the modulation of STEP activity.

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