Does GRK–β arrestin machinery work as a “switch on” for GPR17-mediated activation of intracellular signaling pathways?

Mar 12, 2014Cellular signalling

Does the GRK-beta arrestin system act as a switch to turn on signals inside cells through GPR17?

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Abstract

CysLT-mediated receptor desensitization primarily involves GRK2, which is crucial for OPC maturation.

GPR17 expression and activity regulation may be impaired during oligodendrocyte-precursor cell differentiation.
Different isoforms of GRK are recruited by purinergic and cysteinyl-leukotriene ligands to modulate GPR17 responses.
GRK2 promotes receptor desensitization, transient binding to β-arrestins, rapid ERK phosphorylation, and sustained nuclear CREB activation during cysLT exposure.
GRK5 is exclusively recruited by purinergic ligands, leading to a stable receptor/β-arrestin association and slower ERK stimulation.
The recruitment of specific GRK isoforms by different ligands may activate distinct intracellular pathways that converge on similar outcomes.

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During oligodendrocyte-precursor cell (OPC) differentiation program, an impairment in the regulatory mechanisms controlling GPR17 spatio-temporal expression and functional activity has been suggested to contribute to defective OPC maturation, a crucial event in the pathogenesis of multiple sclerosis. GRK-β arrestin machinery is the primary actor in the control of G-protein coupled receptor (GPCR) functional responses and changes in these regulatory protein activities have been demonstrated in several immune/inflammatory diseases. Herein, in order to shed light on the molecular mechanisms controlling GPR17 regulatory events during cell differentiation, the role of GRK/β-arrestin machinery in receptor desensitization and signal transduction was investigated, in transfected cells and primary OPC. Following cell treatment with the two classes of purinergic and cysteinyl-leukotriene (cysLT) ligands, different GRK isoforms were recruited to regulate GPR17 functional responses. CysLT-mediated receptor desensitization mainly involved GRK2; this kinase, via a G protein-dependent mechanism, promoted a transient binding of the receptor to β-arrestins, rapid ERK phosphorylation and sustained nuclear CREB activation. Furthermore, GRK2, whose expression parallels that of the receptor during differentiation process, appeared to be crucial to induce cysLT-mediated maturation of OPCs. On the other hand, purinergic ligand exclusively recruited the GRK5 subtype, and induced, via a G protein-independent/β-arrestin-dependent mechanism, a receptor/β-arrestin stable association, slower and sustained ERK stimulation and marginal CREB activation. These results show that purinergic and cysLT ligands, through the recruitment of specific GRK isoforms, address distinct intracellular pathways, most likely reinforcing the same final response. The identification of these mechanisms and players controlling GPR17 responses during OPC differentiation could be useful to identify new targets in demyelination diseases and to develop new therapeutical strategies.

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Does GRK–β arrestin machinery work as a “switch on” for GPR17-mediated activation of intracellular signaling pathways?

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