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

Dysfunction of adenosine heteroreceptor complexes can contribute to mental disorder development (Borroto-Escuela et al., 2018a; Beggiato et al., 2021; Merighi et al., 2021). Furthermore, a molecular basis for learning and memory was proposed to be formed through reorganization of available adenosine homo- and heteroreceptor complexes as to structural functions and/or by resetting the multiple allosteric receptor-receptor interactions in these complexes. Based on this evidence, this Opinion article is focused on the underlying relevance of adenosine heteroreceptor complexes in the brain and their integrative mechanisms at the molecular level, involving allosteric receptor-receptor interactions and dephosphorylation mechanisms through Striatal-Enriched Protein Tyrosine Phosphatase (STEP) (Franco et al., 2020b; Yasuda, 2020; Borroto-Escuela et al., 2021a; Barresi et al., 2021; Borroto-Escuela et al., 2021b; Beggiato et al., 2021; Domenici et al., 2021). This enzyme is a tyrosine phosphatase specific to the brain and its substrate is represented by a vast network of synaptic and extra synaptic proteins (Lombroso et al., 1993; Won et al., 2019). Several splice variants exist, namely STEP61, STEP46, STEP38, and STEP20. However, only STEP46 is enriched in the striatum and STEP61 shows a widespread distribution with high densities e.g., in cerebral cortex and hippocampus (Won and Roche, 2021). STEP has several functions through it dephosphorylation, via its enzymatic activity, of synaptic and extra synaptic proteins including kinases and glutamate receptors like NMDARs and AMPARs producing synaptic downregulation (Zhang et al., 2008; Won et al., 2019; Won and Roche, 2021). STEP dysfunction may therefore lead to disturbances in synaptic plasticity necessary for cognition. How STEP and adenosine A2A heteroreceptor complexes can modulate between each other and have a role in molecular integration of adenosine signal in the brain, is the focus of this opinion article.