Purinergic and cysteinyl-leukotriene agonists of the GPR17 receptor engender distinct intracellular signalling programs with different functional potentials in oligodendrocyte maturation
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Data di Pubblicazione:
2013
Citazione:
Purinergic and cysteinyl-leukotriene agonists of the GPR17 receptor engender distinct
intracellular signalling programs with different functional potentials in oligodendrocyte maturation / S. Daniele, M.L. Trincavelli, M. Fumagalli, E. Zappelli, E. Bonfanti, D. Lecca, C. Giacomelli, M.P. Abbracchio, C. Martini. ((Intervento presentato al convegno Neuroscience meeting planner tenutosi a San Diego nel 2013.
Abstract:
GPR17 is a dual receptor activated by both uracil nucleotides and cysteinyl-leukotrienes, mediators involved in trophic responses and in the repair of central nervous system lesions (Ciana et al., EMBO J, 2006). In both brain and spinal cord, GPR17 is transiently expressed by a subpopulation of Oligodendrocyte Precursor Cells (OPCs), in transition from precursors to premyelinating phenotypes. Loss of GPR17 at a relatively advanced differentiation state is a prerequisite to allow terminal maturation: the forced expression of the receptor at late OPC stages impaired terminal maturation (Fumagalli et al., 2011) and induced mice precocious death (Chen et al., 2009). A current hypothesis is that, by binding to GPR17, its endogenous ligands can first induce early precursor cells to undergo differentiation and then switch the receptor off by agonist-induced desensitization via GRK/β-arrestins, thus allowing cells’ terminal maturation. Thus, by controlling the active state of receptors at the plasma membrane, agonist-mediated GPR17 desensitization/internalization finely regulates cells’ progression along their differentiation pathway. Moreover, besides serving to turn-off its biological response, reversible agonist-induced GPR17 internalization may act as an "on" switch sustaining long-term signalling and inducing nuclear events at the basis of OPC terminal maturation. Using primary OPC cultures, in parallel with a transfected cell line, we investigated the role of the GRK/β-arrestin machinery in GPR17 desensitization. We show that the two classes of ligands recruit the same GPCR to engender distinct and different intracellular signalling pathways associated with highly diverse biological responses. Specifically, by a G protein-dependent mechanism, LTD4 promoted GRK2-dependent receptor desensitization, followed by transient binding of GPR17 to β-arrestins, rapid induction of ERK phosphorylation, and sustained nuclear CREB activation. Viceversa, by a completely G protein-independent/β-arrestin-dependent mechanism, UDP-glucose recruited GRK5 as a primary kinase, induced a stable association of GPR17 to β-arrestins, a slower and more sustained ERK stimulation and a mild CREB activation.
Thus, by acting on GPR17, cysLTs activate signalling pathways culminating in transcriptional effects, while purinergic ligands mainly influence cytosolic events. These results suggest that activation of distinct signalling program by different classes of endogenous GPR17 ligands may have distinct functional potentials in controlling OPC myelination.
Tipologia IRIS:
14 - Intervento a convegno non pubblicato
Elenco autori:
S. Daniele, M.L. Trincavelli, M. Fumagalli, E. Zappelli, E. Bonfanti, D. Lecca, C. Giacomelli, M.P. Abbracchio, C. Martini
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