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

Daniele, Simona; Trincavelli, Maria Letizia; Fumagalli, Marta; Zappelli, Elisa; Lecca, Davide; Bonfanti, Elisabetta; Campiglia, Pietro; Abbracchio, Maria P.; Martini, Claudia

doi:10.1016/j.cellsig.2014.02.016

Cited by 35 publications

(45 citation statements)

References 38 publications

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“…Similarly, lipophilic statins may exert neurotrophic functions through the transcriptional activation of CREB and consequent BDNF increase53. Besides, the phosphorylation of CREB is also part of the cascade triggered during benztropine-induced oligodendrocyte differentiation20 and is involved in the regulation of OPC differentiation by GPR17, another potential target for the treatment of myelin damage54.…”

Section: Discussionmentioning

confidence: 99%

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

Eleuteri

Olla

Veroni

et al. 2017

Sci Rep

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There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds’ activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan.

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Section: Discussionmentioning

confidence: 99%

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

Eleuteri

Olla

Veroni

et al. 2017

Sci Rep

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“…Consistently, two‐photon imaging of adult NG2+ cells in vivo showed that most differentiating oligodendrocytes in the intact cortex are not recently generated and highlighted a remarkable heterogeneity of oligodendroglial maturation rates (Hughes et al, ). Previous studies have reported that cells have to downregulate GPR17 before acquiring myelin proteins (Boda et al, ; Fumagalli et al, ) and that forced expression of the receptor in oligodendroglia inhibits terminal maturation (Chen et al, ; Daniele et al, ). Of note, GPR17 expression on cell surface is regulated by extrinsic signals, indicating a prominent role of environmental cues in determining the length of the GPR17+ phase (Daniele et al, ; Fratangeli et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have reported that cells have to downregulate GPR17 before acquiring myelin proteins (Boda et al, ; Fumagalli et al, ) and that forced expression of the receptor in oligodendroglia inhibits terminal maturation (Chen et al, ; Daniele et al, ). Of note, GPR17 expression on cell surface is regulated by extrinsic signals, indicating a prominent role of environmental cues in determining the length of the GPR17+ phase (Daniele et al, ; Fratangeli et al, ). Further, we found that about a third of the newborn OPCs re‐enter cell cycle after 7 days in the juvenile cortex.…”

Section: Discussionmentioning

confidence: 99%

Early phenotypic asymmetry of sister oligodendrocyte progenitor cells after mitosis and its modulation by aging and extrinsic factors

Boda

Maria

Rosa

et al. 2014

Glia

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Oligodendrocyte progenitor cells (OPCs) persist in the adult central nervous system and guarantee oligodendrocyte turnover throughout life. It remains obscure how OPCs avoid exhaustion during adulthood. Similar to stem cells, OPCs could self-maintain by undergoing asymmetric divisions generating a mixed progeny either keeping a progenitor phenotype or proceeding to differentiation. To address this issue, we examined the distribution of stage-specific markers in sister OPCs during mitosis and later after cell birth, and assessed its correlation with distinct short-term fates. In both the adult and juvenile cerebral cortex a fraction of dividing OPCs gives rise to sister cells with diverse immunophenotypic profiles and short-term behaviors. Such heterogeneity appears as cells exit cytokinesis, but does not derive from the asymmetric segregation of molecules such as NG2 or PDGFRa expressed in the mother cell. Rather, rapid downregulation of OPC markers and upregulation of molecules associated with lineage progression contributes to generate early sister OPC asymmetry. Analyses during aging and upon exposure to physiological (i.e., increased motor activity) and pathological (i.e., trauma or demyelination) stimuli showed that both intrinsic and environmental factors contribute to determine the fraction of symmetric and asymmetric OPC pairs and the phenotype of the OPC progeny as soon as cells exit mitosis.

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“…Following agonist activation, GPR17 undergoes barrestin/clathrin-mediated internalization in early endosomes, and is subsequently sorted to lysosomes for degradation or to recycling endosomes for re-incorporation into the plasma membrane (Daniele et al, 2014;Fratangeli et al, 2013, Hennen et al, 2013. The balance between degradation and recycling regulates the number of receptors at the cell surface, with important implications in the silencing or activation of GPR17-signaling pathways and, possibly, in OL differentiation.…”

Section: Introductionmentioning

confidence: 99%

SNX27, a protein involved in down syndrome, regulates GPR17 trafficking and oligodendrocyte differentiation

Meraviglia

Ulivi

Boccazzi

et al. 2016

Glia

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The G protein-coupled receptor 17 (GPR17) plays crucial roles in myelination. It is highly expressed during transition of oligodendrocyte progenitor cells to immature oligodendrocytes, but, after this stage, it must be down-regulated to allow generation of mature myelinating cells. After endocytosis, GPR17 is sorted into lysosomes for degradation or recycled to the plasma membrane. Balance between degradation and recycling is important for modulation of receptor levels at the cell surface and thus for the silencing/activation of GPR17-signaling pathways that, in turn, affect oligodendrocyte differentiation. The molecular mechanisms at the basis of these processes are still partially unknown and their characterization will allow a better understanding of myelination and provide cues to interpret the consequences of GPR17 dysfunction in diseases. Here, we demonstrate that the endocytic trafficking of GPR17 is mediated by the interaction of a type I PDZ-binding motif located at the C-terminus of the receptor and SNX27, a recently identified protein of the endosome-associated retromer complex and whose functions in oligodendrocytes have never been studied. SNX27 knock-down significantly reduces GPR17 plasma membrane recycling in differentiating oligodendrocytes while accelerating cells' terminal maturation. Interestingly, trisomy-linked down-regulation of SNX27 expression in the brain of Ts65Dn mice, a model of Down syndrome, correlates with a decrease in GPR17(+) cells and an increase in mature oligodendrocytes, which, however, fail in reaching full maturation, eventually leading to hypomyelination. Our data demonstrate that SNX27 modulates GPR17 plasma membrane recycling and stability, and that disruption of the SNX27/GPR17 interaction might contribute to pathological oligodendrocyte differentiation defects. GLIA 2016. GLIA 2016;64:1437-1460.

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

Cited by 35 publications

References 38 publications

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

Early phenotypic asymmetry of sister oligodendrocyte progenitor cells after mitosis and its modulation by aging and extrinsic factors

SNX27, a protein involved in down syndrome, regulates GPR17 trafficking and oligodendrocyte differentiation

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