G Protein-Coupled Receptors in Myelinating Glia

Abstract

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 G-protein coupled receptor GPR126 in Schwann cells is essential for both developmental myelination and re-myelination (Mogha, D'Rozario, & Monk, 2016;Mogha, Harty, et al, 2016). This protein is not required for the maintenance of myelin in uninjured nerves, but inactivation of Gpr126 in repair Schwann cells results in reduced axonal regeneration, reduced expression of TNF and a restricted group of chemokines, and impaired recruitment of macrophages, cells which potentially promote axonal regeneration (Barrette et al, 2008).…”

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“…Available evidence has suggested that Schwann cells (SC) require signaling from the cAMP to initiate the myelination program. This idea is supported by studies on isolated SC showing as prolonged cAMP stimulation increases the expression of proteins and lipids specific to the myelinating SC phenotype . In addition, different works showed that elevation of cAMP levels in SC is dependent by GPR126 protein, a highly conserved orphan G protein‐coupled receptor, critical for myelination within the peripheral nervous system (PNS) during development .…”

“…This idea is supported by studies on isolated SC showing as prolonged cAMP stimulation increases the expression of proteins and lipids specific to the myelinating SC phenotype . In addition, different works showed that elevation of cAMP levels in SC is dependent by GPR126 protein, a highly conserved orphan G protein‐coupled receptor, critical for myelination within the peripheral nervous system (PNS) during development . Interestingly, biallelic loss‐of‐function mutations in GPR126 are responsible for a lethal form of AMC (LCCS9, MIM # 616503) …”