In oligodendrocyte precursor cells (OPCs) the new P2Y-like receptor GPR17 expression is restricted to early stages of differentiation and segregated from that of mature myelin proteins to the point that mature oligodendrocytes no longer express the receptor1,2. The changes in GPR17 expression during olygodendrocyte differentiation suggest that this receptor may undergo regulatory mechanisms such as desensitization, internalization and down regulation that regulate its responsiveness over time. On this basis, we analyzed, in a recombinant expression system, GPR17 regulation after prolonged agonist exposure. GPR17 is activated by both uracil-nucleotides (i.e. UDP-glucose3) and cysteynyl-leukotrienes (cysLTs) (i.e. LTD43). We demonstrated that both cysLT and purinergic ligands induced a time- and concentration-dependent GPR17 loss of response; this phenomenon was accompanied by receptor internalization. Upon agonist removal, receptor resensitization occurred with the typical kinetics of GPCR. Moreover, activation of GPR17 by UDP-glucose (but not viceversa) induced a partial heterologous desensitization of LTD4-mediated responses, suggesting that nucleotides have a hierarchy in producing desensitizing signals. Finally, we showed that GPR17 desensitization occurs as a consequence of receptor phosphorylation on serine and threonine residues, through a mechanism likely involving GRK activation. Since GRK expression and functioning has been demonstrated to be altered in several neurodegenerative diseases, including multiple sclerosis4, studies are in progress to evaluate GRK2 expression and GRK2-mediated GPR17 regulation during OPC maturation, both in physiological and pathological conditions. The determination of the regulatory mechanisms controlling GPR17 responses over time is pivotal to find new ways to foster OPC differentiation and myelin repair in demyelinating diseases.
Regulation Of The P2Y-Like Receptor GPR17 By Agonist-Induced Desensitization
DANIELE, SIMONA;TRINCAVELLI, MARIA LETIZIA;GIACOMELLI, CHIARA;MARTINI, CLAUDIA
2012-01-01
Abstract
In oligodendrocyte precursor cells (OPCs) the new P2Y-like receptor GPR17 expression is restricted to early stages of differentiation and segregated from that of mature myelin proteins to the point that mature oligodendrocytes no longer express the receptor1,2. The changes in GPR17 expression during olygodendrocyte differentiation suggest that this receptor may undergo regulatory mechanisms such as desensitization, internalization and down regulation that regulate its responsiveness over time. On this basis, we analyzed, in a recombinant expression system, GPR17 regulation after prolonged agonist exposure. GPR17 is activated by both uracil-nucleotides (i.e. UDP-glucose3) and cysteynyl-leukotrienes (cysLTs) (i.e. LTD43). We demonstrated that both cysLT and purinergic ligands induced a time- and concentration-dependent GPR17 loss of response; this phenomenon was accompanied by receptor internalization. Upon agonist removal, receptor resensitization occurred with the typical kinetics of GPCR. Moreover, activation of GPR17 by UDP-glucose (but not viceversa) induced a partial heterologous desensitization of LTD4-mediated responses, suggesting that nucleotides have a hierarchy in producing desensitizing signals. Finally, we showed that GPR17 desensitization occurs as a consequence of receptor phosphorylation on serine and threonine residues, through a mechanism likely involving GRK activation. Since GRK expression and functioning has been demonstrated to be altered in several neurodegenerative diseases, including multiple sclerosis4, studies are in progress to evaluate GRK2 expression and GRK2-mediated GPR17 regulation during OPC maturation, both in physiological and pathological conditions. The determination of the regulatory mechanisms controlling GPR17 responses over time is pivotal to find new ways to foster OPC differentiation and myelin repair in demyelinating diseases.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.