UDP-glucose enhances outward K+ currents necessary for cell differentiation and stimulates cell migration by activating the GPR17 receptor in oligodendrocyte precursors

• Published in: Glia Vol. 61; no. 7; pp. 1155 - 1171
• Main Authors: Coppi, Elisabetta, Maraula, Giovanna, Fumagalli, Marta, Failli, Paola, Cellai, Lucrezia, Bonfanti, Elisabetta, Mazzoni, Luca, Coppini, Raffaele, Abbracchio, Maria P., Pedata, Felicita, Pugliese, Anna Maria
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-07-2013; Wiley Subscription Services, Inc
• Subjects: Adenosine Diphosphate - analogs & derivatives; Adenosine Diphosphate - pharmacology; Animals; Animals, Newborn; Antigens - metabolism; Brain - cytology; Ca2+ currents; Calcium - metabolism; Cell Differentiation - drug effects; Cell Movement - drug effects; Cells, Cultured; Glial Fibrillary Acidic Protein - metabolism; Glucose; GPR17; K+ currents; Membrane Potentials - drug effects; migration; myelination; Oligodendroglia - drug effects; Oligodendroglia - metabolism; Potassium Channel Blockers - pharmacology; Potassium Channels - metabolism; Proteoglycans - metabolism; Purinergic P2Y Receptor Antagonists - pharmacology; purinergic receptors; Rats; Rats, Wistar; Receptors, G-Protein-Coupled - metabolism; Sodium Channel Blockers - pharmacology; Stem Cells; Tetraethylammonium - pharmacology; Tetrodotoxin - pharmacology; Uridine Diphosphate Glucose - pharmacology
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.22506

In the developing and mature central nervous system, NG2 expressing cells comprise a population of cycling oligodendrocyte progenitor cells (OPCs) that differentiate into mature, myelinating oligodendrocytes (OLGs). OPCs are also characterized by high motility and respond to injury by migrating into the lesioned area to support remyelination. K+ currents in OPCs are developmentally regulated during differentiation. However, the mechanisms regulating these currents at different stages of oligodendrocyte lineage are poorly understood. Here we show that, in cultured primary OPCs, the purinergic G‐protein coupled receptor GPR17, that has recently emerged as a key player in oligodendrogliogenesis, crucially regulates K+ currents. Specifically, receptor stimulation by its agonist UDP‐glucose enhances delayed rectifier K+ currents without affecting transient K+ conductances. This effect was observed in a subpopulation of OPCs and immature pre‐OLGs whereas it was absent in mature OLGs, in line with GPR17 expression, that peaks at intermediate phases of oligodendrocyte differentiation and is thereafter downregulated to allow terminal maturation. The effect of UDP‐glucose on K+ currents is concentration‐dependent, blocked by the GPR17 antagonists MRS2179 and cangrelor, and sensitive to the K+ channel blocker tetraethyl‐ammonium, which also inhibits oligodendrocyte maturation. We propose that stimulation of K+ currents is responsible for GPR17‐induced oligodendrocyte differentiation. Moreover, we demonstrate, for the first time, that GPR17 activation stimulates OPC migration, suggesting an important role for this receptor after brain injury. Our data indicate that modulation of GPR17 may represent a strategy to potentiate the post‐traumatic response of OPCs under demyelinating conditions, such as multiple sclerosis, stroke, and brain trauma.