AUTHOR=Coppi Elisabetta , Cencetti Francesca , Cherchi Federica , Venturini Martina , Donati Chiara , Bruni Paola , Pedata Felicita , Pugliese Anna Maria 

TITLE=A2B Adenosine Receptors and Sphingosine 1-Phosphate Signaling Cross-Talk in Oligodendrogliogenesis

JOURNAL=Frontiers in Neuroscience

VOLUME=15

YEAR=2021

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2021.677988

DOI=10.3389/fnins.2021.677988

ISSN=1662-453X

ABSTRACT=<p>Oligodendrocyte-formed myelin sheaths allow fast synaptic transmission in the brain. Impairments in the process of myelination, or demyelinating insults, might cause chronic diseases such as multiple sclerosis (MS). Under physiological conditions, remyelination is an ongoing process throughout adult life consisting in the differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes (OLs). During pathological events, this process fails due to unfavorable environment. Adenosine and sphingosine kinase/sphingosine 1-phosphate signaling axes (SphK/S1P) play important roles in remyelination processes. Remarkably, fingolimod (FTY720), a sphingosine analog recently approved for MS treatment, plays important roles in OPC maturation. We recently demonstrated that the selective stimulation of A<sub>2</sub><sub><italic>B</italic></sub> adenosine receptors (A<sub>2</sub><sub><italic>B</italic></sub>Rs) inhibit OPC differentiation <italic>in vitro</italic> and reduce voltage-dependent outward K<sup>+</sup> currents (I<sub><italic>K</italic></sub>) necessary to OPC maturation, whereas specific SphK1 or SphK2 inhibition exerts the opposite effect. During OPC differentiation A<sub>2</sub><sub><italic>B</italic></sub>R expression increases, this effect being prevented by SphK1/2 blockade. Furthermore, selective silencing of A<sub>2</sub><sub><italic>B</italic></sub>R in OPC cultures prompts maturation and, intriguingly, enhances the expression of S1P lyase, the enzyme responsible for irreversible S1P catabolism. Finally, the existence of an interplay between SphK1/S1P pathway and A<sub>2</sub><sub><italic>B</italic></sub>Rs in OPCs was confirmed since acute stimulation of A<sub>2</sub><sub><italic>B</italic></sub>Rs activates SphK1 by increasing its phosphorylation. Here the role of A<sub>2</sub><sub><italic>B</italic></sub>R and SphK/S1P signaling during oligodendrogenesis is reviewed in detail, with the purpose to shed new light on the interaction between A<sub>2</sub><sub><italic>B</italic></sub>Rs and S1P signaling, as eventual innovative targets for the treatment of demyelinating disorders.</p>