Adenosine STEPs on synaptic function

Abstract

This is an Editorial Highlight of a manuscript by Mallozzi et al. (2019) in the current issue of the Journal of Neurochemistry, in which the authors detail the biochemical pathway that leads to synaptic depression by cocaine. This pathway requires the adenosine A2A receptor and STEP phosphatases. Activation of the adenosine A2A receptor leads to an increase in intracellular calcium, activation of STEP by dephosphorylation, inhibition of excitatory ionotropic glutamate receptors by dephosphorylation of phospho‐tyrosine residues and subsequent internalization of the ionotropic glutamate receptors. This adenosine A2A receptor pathway could lead to potential drug targets for neurologic and neuropsychiatric disorders.

The coming together of allosteric and phosphorylation mechanisms in the molecular integration of A2A heteroreceptor complexes in the dorsal and ventral striatal-pallidal GABA neurons

“…Changes induced in striatal synaptic glutamate transmission were modulated by cocaine (10 µM) by an increase in adenosine levels and the consequent A2AR activation, a mechanism involving the participation of STEP [3] and mediating the A2AR agonist-induced reduction in cocaine self-administration. The possible involvement of A2AR-dopamine (DA) D2R heteroreceptor complex in STEP-mediated A2AR agonist-induced reduction in cocaine self-administration has also be proposed by R. Yasuda in its Editorial [1]. In this heteroreceptor complex, the A2AR protomer allosterically inhibits the DA D2R protomer signaling in the ventral striatal-pallidal GABA neurons [4,5], leading to an inhibition of cocaine self-administration [6][7][8],…”

“…The major activation of STEP takes place through activated calcineurin turning on protein phosphatase 1, producing a dephosphorylation of STEP which causes activation of STEP [1]. As to removal of STEP, it was demonstrated that ubiquitination of STEP is produced by synaptic activation causing its degradation.…”

“…In its Editorial [1], Robert Yasuda focused on having a general mechanism by which STEP is modulated by A2AR upon its activation in neurons expressing A2AR and D2R, which can include also neuroblastoma cell lines, known to express these receptors [55]. The modulation of STEP by A2AR involved a calcineurin/PP1 pathway which was calcium dependent [3].…”

“…In a recent Editorial by Robert Yasuda [1] on striatalenriched protein tyrosine phosphatase (STEP) activity in central nervous system (CNS), the role of adenosine and STEP in modulating synaptic glutamate receptor function has been discussed, especially in relation to how STEP might be modulated by the adenosine A2A receptor (A2AR) activation [2]. Changes induced in striatal synaptic glutamate transmission were modulated by cocaine (10 µM) by an increase in adenosine levels and the consequent A2AR activation, a mechanism involving the participation of STEP [3] and mediating the A2AR agonist-induced reduction in cocaine self-administration.…”

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

“…Moreover, the involvement of calcineurin suggests the need of intracellular calcium increase. These mechanisms have been very nicely examined and depicted by Robert Yasuda (Yasuda, 2020) who recapitulated the way through which A 2A R modulates cocaine-induced synaptic depression and, possibly, cocaine self-administration, via STEP activation.…”