Abstract
The STriatal-Enriched protein tyrosine phosphatase STEP is a brain-specific tyrosine phosphatase that plays a pivotal role in the mechanisms of learning and memory, and it has been demonstrated to be involved in several neuropsychiatric diseases. Recently, we found a functional interaction between STEP and adenosine A2A receptor (A2AR), a subtype of the adenosine receptor family widely expressed in the central nervous system, where it regulates motor behavior and cognition, and plays a role in cell survival and neurodegeneration. Specifically, we demonstrated the involvement of STEP in A2AR-mediated cocaine effects in the striatum and, more recently, we found that in the rat striatum and hippocampus, as well as in a neuroblastoma cell line, the overexpression of the A2AR, or its stimulation, results in an increase in STEP activity. In the present article we will discuss the functional implication of this interaction, trying to examine the possible mechanisms involved in this relation between STEP and A2ARs.
Highlights
P1 adenosine receptors are the most investigated purinergic receptors within the central nervous system (CNS)
In order to understand the relationship among cocaine, A2A receptor (A2AR) and tyrosine phosphatases, we evaluated the enzimatic activity of the total tyrosine phosphatases, and of STEP in particular, in mice striatal tissue after cocaine stimulation
We found a significant increase in STEP activity in the striatum and hippocampus of A2AR overexpressing rats with respect to wild type
Summary
P1 adenosine receptors are the most investigated purinergic receptors within the central nervous system (CNS). In a recent paper Won and collaborators used mass spectrometry to study STEP binding proteins and identified 315 candidate proteins and, among them, the authors recognized mGlu5R as an interactor of STEP (Won et al, 2019) This finding is interesting since it is well known that A2AR and mGlu5R physically and functionally interact in several brain areas, that activation of A2ARs exerts a permissive role on mGluR5R-mediated effects (Ferre et al, 2002; Domenici et al, 2004; Tebano et al, 2005; Krania et al, 2018) and, most importantly, that mGlu5R stimulation results in an increase in STEP translation and, presumably, activation (Zhang et al, 2008). Even though additional experiments are needed, these results clearly suggest that A2ARs modulate STEP activity through the involvement of mGlu5R (Figure 1)
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