The adhesion GPCR Gpr56 regulates oligodendrocyte development via interactions with Gα12/13 and RhoA

Ackerman, Sarah D.; Garcia, Claudia M.; Piao, Xiangshu; Gutmann, David H.; Monk, Kelly R.

doi:10.1038/ncomms7122

Cited by 131 publications

(150 citation statements)

References 64 publications

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“…For example, the aGPCR GPR56/ADGRG1 is involved in cortex development, oligodendrocyte development, muscle cell development, innate immunity, and cancer progression (11)(12)(13)(14)(15)(16)(17). Recent studies have highlighted the role of GPR56 in promoting progression of acute myeloid leukemia (18) and progastrin-dependent colon cancer (19) and suggested that a GPR56 inhibitor would be clinically desirable.…”

mentioning

confidence: 99%

Stachel-independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

Salzman

Zhang

Gupta

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

105

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Adhesion G protein-coupled receptors (aGPCRs) play critical roles in diverse biological processes, including neurodevelopment and cancer progression. aGPCRs are characterized by large and diverse extracellular regions (ECRs) that are autoproteolytically cleaved from their membrane-embedded signaling domains. Although ECRs regulate receptor function, it is not clear whether ECRs play a direct regulatory role in G-protein signaling or simply serve as a protective cap for the activating "Stachel" sequence. Here, we present a mechanistic analysis of ECR-mediated regulation of GPR56/ADGRG1, an aGPCR with two domains [pentraxin and laminin/neurexin/sex hormonebinding globulin-like (PLL) and G protein-coupled receptor autoproteolysis-inducing (GAIN)] in its ECR. We generated a panel of high-affinity monobodies directed to each of these domains, from which we identified activators and inhibitors of GPR56-mediated signaling. Surprisingly, these synthetic ligands modulated signaling of a GPR56 mutant defective in autoproteolysis and hence, in Stachel peptide exposure. These results provide compelling support for a ligandinduced and ECR-mediated mechanism that regulates aGPCR signaling in a transient and reversible manner, which occurs in addition to the Stachel-mediated activation.adhesion GPCR | allostery | cell signaling | monobody | protein engineering

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mentioning

confidence: 99%

Stachel-independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

Salzman

Zhang

Gupta

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

105

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“…Conversely, sustained activation of either PKC or ROCK2 is associated with less efficient differentiation. Indeed, the adhesion receptor GPR56 has recently been shown to inhibit oligodendrocyte myelination in zebrafish via activation of the G␣ 12/13 -RhoA-ROCK pathway (9). Furthermore, down-regulation of the adenylyl cyclase-cyclic-adenosine 3Ј,5Ј-monophosphate (cAMP)-PKA-CREB cascade also impairs oligodendrocyte differentiation (10 -12).…”

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confidence: 99%

The Orphan G Protein-coupled Receptor GPR17 Negatively Regulates Oligodendrocyte Differentiation via Gαi/o and Its Downstream Effector Molecules

Simon

Hennen

Merten

et al. 2016

Journal of Biological Chemistry

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Recent studies have recognized G protein-coupled receptors as important regulators of oligodendrocyte development. GPR17, in particular, is an orphan G protein-coupled receptor that has been identified as oligodendroglial maturation inhibitor because its stimulation arrests primary mouse oligodendrocytes at a less differentiated stage. However, the intracellular signaling effectors transducing its activation remain poorly understood. Here, we use Oli-neu cells, an immortalized cell line derived from primary murine oligodendrocytes, and primary rat oligodendrocyte cultures as model systems to identify molecular targets that link cell surface GPR17 to oligodendrocyte maturation blockade. We demonstrate that stimulation of GPR17 by the small molecule agonist MDL29,951 (2-carboxy-4,6-dichloro-1H-indole-3-propionic acid) decreases myelin basic protein expression levels mainly by triggering the G␣ i/o signaling pathway, which in turn leads to reduced activity of the downstream cascade adenylyl cyclase-cAMP-PKA-cAMP response element-binding protein (CREB). In addition, we show that GPR17 activation also diminishes myelin basic protein abundance by lessening stimulation of the exchange protein directly activated by cAMP (EPAC), thus uncovering a previously unrecognized role for EPAC to regulate oligodendrocyte differentiation. Together, our data establish PKA and EPAC as key downstream effectors of GPR17 that inhibit oligodendrocyte maturation. We envisage that treatments augmenting PKA and/or EPAC activity represent a beneficial approach for therapeutic enhancement of remyelination in those demyelinating diseases where GPR17 is highly expressed, such as multiple sclerosis.Myelination is a central nervous system (CNS) process where oligodendrocytes establish myelin sheaths that stabilize, protect, and electrically insulate neuronal axons. During postnatal development, oligodendrocytes progress through a sequence of differentiation steps from oligodendrocyte precursor cells (OPCs) 5 to myelinating mature oligodendrocytes (1). Failure during this process leads to impaired myelination and, consequently, to slow conduction of signals along nerves, which results in debilitating symptoms such as paralysis and cognitive impairments. Likewise, in many severe neurological disorders, among others multiple sclerosis (MS), loss of oligodendrocytes and destruction of CNS myelin precedes the serious neurological deficits. Although OPCs are abundant in chronic MS lesion sites, no remyelination occurs, which suggests that oligodendrocyte differentiation does not take place due to either the absence of pro-myelinating signals or presence of myelination inhibitors in the MS lesion (2, 3).During the previous years, an increasing number of oligodendroglial differentiation inhibitors have been identified (for review see Ref. 4). Genetic evidence from transgenic mice supports the notion that the orphan G protein-coupled receptor GPR17 (5) negatively regulates oligodendrocyte maturation and myelination (6). Notably, GPR17 is highly abundant...

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“…That human patients with GPR56/ADGRG1 mutations present with white matter defects underscores the clinical importance of this adhesion GPCR in CNS myelination [68]. Gpr56-dependent OPC proliferation is mediated by Gα 12/13 -RhoA signaling [66,67], although the activating ligand for Gpr56/Adgrg1 in OPCs is currently unknown. In other cellular contexts, Gpr56/Adgrg1 can bind the ECM proteins tissue transglutaminase (TG2) and collagen III [69,70], and in the future it will be interesting to determine if either of these molecules activates Gpr56/Adgrg1 in OPCs.…”

Section: Adhesion Gpcrs In Oligodendrocyte Developmentmentioning

confidence: 99%

“…In the CNS, Gpr17 has been explored as a potential therapeutic target in remyelination either by inhibiting Gpr17 via antagonists or by activating the reserve pool of Gpr17-expressing OPCs to maturation [79,80]. As Gpr17 is enriched in white matter plaques of MS patients and in rodent models of MS, antagonism of Gpr17 or other inhibitory GPCRs may indeed be efficacious in future treatment strategies [57,64,66,67]. Additional GPCRs have been implicated in CNS myelin repair including Cxcr4, Gpr30, endothelin receptors, and sphingosine 1-phosphate receptors [81][82][83][84][85], underscoring the importance of this receptor super-family in myelin health and disease.…”

Section: Pharmacological Implications Of Gpcrs In Myelin Diseasesmentioning

confidence: 99%

“…Gpr56/Adgrg1 belongs to the same adhesion GPCR subfamily as Gpr126/Adgrg6 [10]. In the CNS, Gpr56/Adgrg1 is expressed in several cell types including OPCs, where this adhesion GPCR functions cell autonomously as an evolutionarily conserved regulator of OPC proliferation and differentiation [66,67]. In zebrafish and mouse Gpr56/Adgrg1 loss-of-function mutants, OPCs precociously differentiate before the full cohort of these cells are established such that hypomyelination is observed in later development.…”

mentioning

confidence: 99%

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G Protein-Coupled Receptors in Myelinating Glia

Mogha¹,

D’Rozario²,

Monk

2017

Trends in Pharmacological Sciences

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The G protein-coupled receptor (GPCR) super-family represents the largest class of functionally selective drug targets for disease modulation and therapy. GPCRs have been studied in great detail in central nervous system (CNS) neurons, yet these important molecules have been relatively understudied in glia. In recent years, however, exciting new roles for GPCRs in glial cell biology have emerged. Here, we focus on key roles for GPCRs in a specialized subset of glia, myelinating glia. We highlight recent work firmly establishing GPCRs as regulators of myelinating glial cell development and myelin repair. These advancements expand our understanding of myelinating glial cell biology and underscore the utility of targeting GPCRs to promote myelin repair in human disease. KeywordsG protein-coupled receptor (GPCR); myelination; Schwann cell; oligodendrocyte; remyelination An overview of G protein-coupled receptors in the nervous systemThe G protein-coupled receptor (GPCR) super-family of seven transmembrane (7TM) receptors comprises the largest class of cell membrane receptors [1]. GPCRs are activated by myriad stimuli including peptides, hormones, light, proteolytic processing of their Ntermini, small molecules, and more traditional protein ligands [2,3]. GPCRs have emerged as major pharmacological drug targets due to their key roles in a variety of physiological functions in disease and health, and GPCR modulators represent at least one-third of all clinically marketed drugs [4]. GPCRs can be classified into five families using the phylogenetically based GRAFS system: glutamate, rhodopsin, adhesion, frizzled, and secretin [5]. Glutamate is a major excitatory neurotransmitter in the nervous system, and * Correspondence: monkk@wustl.edu (K.R. Monk). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of interest statementThe authors declare no competing conflicts. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript accordingly, glutamate receptors have been studied in great detail with regard to their key roles in synaptic transmission, synapse formation, axon guidance, and development of neuronal circuits [6,7]. The rhodopsin family has by far the greatest number of GPCRs, and members are involved in photoreception and neurotransmission [5]. Frizzled GPCRs are activated by wingless/int (Wnt) proteins and control numerous cellular processes including neural crest development, patterning and adult neurogenesis [8]. Secretin receptors are classic hormone receptors, some of which have neuroprotective functions in the central nervou...

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The adhesion GPCR Gpr56 regulates oligodendrocyte development via interactions with Gα12/13 and RhoA

Cited by 131 publications

References 64 publications

Stachel-independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

Stachel-independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

The Orphan G Protein-coupled Receptor GPR17 Negatively Regulates Oligodendrocyte Differentiation via Gαi/o and Its Downstream Effector Molecules

G Protein-Coupled Receptors in Myelinating Glia

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