The activity of the Striatal‐enriched protein tyrosine phosphatase in neuronal cells is modulated by adenosine A_2A receptor

Abstract

We recently demonstrated that a tonic activation of adenosine A2A receptors (A2ARs) is required for cocaine‐induced synaptic depression and increase in the activity of STriatal‐Enriched protein tyrosine Phosphatase (STEP). In this study, we elaborated on the relationship between A2AR and STEP using genetic, pharmacological, and cellular tools. We found that the activities of protein tyrosine phosphatases (PTPs), and in particular of STEP, are significantly increased in the striatum and hippocampus of a transgenic rat strain over‐expressing the neuronal A2AR (NSEA2A) with respect to wild‐type (WT) rats. Moreover the selective A2AR agonist 4‐[2‐[[6‐Amino‐9‐(N‐ethyl‐β‐d‐ribofuranuronamidosyl)‐9H‐purin‐2‐yl]amino]ethyl]benzenepropanoic acid hydrochloride up‐regulates PTPs and STEP activities in WT but not in NSEA2A rats, while the selective A2AR antagonist 4‐(−2‐[7‐amino‐2‐{2‐furyl}{1,2,4}triazolo{2,3‐a} {1,3,5}triazin‐5‐yl‐amino]ethyl)phenol restores the tyrosine phosphatase activities in NSEA2A, having no effects in WT rats. In addition, while cocaine induced the activation of PTP and STEP in WT rats, it failed to increase phosphatase activity in NSEA2A rats. A2ARs modulate STEP activity also in the SH‐SY5Y neuroblastoma cell line, where a calcium‐dependent calcineurin/PP1 pathway was found to play a major role. In summary, the present study identified a novel interaction between A2AR and STEP that could have important clinical implications, since STEP has emerged as key regulator of signaling pathways involved in neurodegenerative and neuropsychiatric diseases and A2ARs are considered a promising target for the development of therapeutic strategies for different diseases of the central nervous system. Read the Editorial Highlight for this article on page https://doi.org/10.1111/jnc.14901

Adenosine STEPs on synaptic function

“…Long access cocaine self‐administration has been shown to decrease the phosphorylation of the STEP phosphatase (an indicator of phosphatase activation) in the prefrontal cortex and increase ionotropic glutamate receptor internalization mediated by dephosphorylation of tyrosine residues on these receptors by STEP (Sun et al, ). In the present study, Mallozzi et al () find that the stimulation of the A 2A R activates STEP phosphatase activity in both the striatum and hippocampus of the wild type (WT) rats. Transgenic rats that overexpress the human A 2A R (NSEA 2A rats) possess increased basal protein tyrosine phosphatase activity including STEP in both the striatum and hippocampus.…”

“…The manuscript in this issue of Journal of Neurochemistry by Mallozzi et al () helps to further understand how cocaine mediates synaptic depression via adenosine A 2A receptor (A 2A R) and the A 2A R activation of Striatal‐Enriched Protein Tyrosine Phosphatase (STEP). Cocaine increases the brain levels of adenosine which increases the stimulation of the A 2A R (Fiorillo and Williams, ; Kubrusly and Bhide, ).…”

“…Chiodi et al () found FK506, a calcineurin inhibitor, blocks the synaptic depression. Since calcineurin is calcium‐dependent, the authors examined how an A 2A R agonist (CGS21680) would affect intracellular calcium in human SH‐SY5Y cells (Mallozzi et al, ). They found that a A 2A R agonist increases the amount of intracellular calcium while the rise in intracellular calcium can be blunted by an A 2A R antagonist.…”

“…The paper by Mallozzi et al () has increased our understanding of the cocaine/A 2A R/STEP pathway that leads to synaptic depression. It clearly demonstrates that stimulation of the A 2A R causes a rise in the intracellular calcium levels that could activate the calcineurin/DARPP32/PP1 (CDP) pathway.…”

Insight into the Role of the STriatal-Enriched Protein Tyrosine Phosphatase (STEP) in A2A Receptor-Mediated Effects in the Central Nervous System

“…Recently, we identified a novel role of A 2A Rs in the rodent brain and in neuronal cells. Specifically, we demonstrated that the stimulation of A 2A Rs results in the activation of the STriatal-Enriched protein tyrosine phosphatase STEP, a brain-specific tyrosine phosphatase involved in several functions, including learning and memory (Goebel-Goody et al, 2012;Chiodi et al, 2014;Mallozzi et al, 2020).…”