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    • G protein coupled receptors GPCRs

    2021-09-10

    G-protein coupled receptors (GPCRs) constitute a large family of 7 trans-membrane-spanning proteins that activate internal signal transduction cascades through binding to different ligands including neurotransmitters, peptides, and lipids [7]. This family of receptors has therapeutic potentials in the treatment of MS [8,9]. The rhodopsin-like or class A family of GPCRs has been recognized as the largest source of therapeutic targets [7,9,10]. Although a large number of rhodopsin-like receptors are called “orphans” and mostly have no known ligand(s) [11]. In this review article, for the first time, we present an overview of the effect(s) of selected orphan GPCRs in the ODM-201 and progression of MS.
    Methods The present review was performed using relevant keywords such as ‘multiple sclerosis’, ‘oligodendrocyte precursor cells’, ‘myelin’, ‘glial cells’, ‘Schwann cells’, ‘GPCRs’, ‘demyelination models’, orphan receptors, ‘cuprizone’, and ‘EAE’ in the following databases: PubMed (U.S. National Library of Medicine, Bethesda, MD), Web of Science (Thomson Reuters, Eagan, MN), and Scopus and ScienceDirect (Elsevier Properties S.A, USA). No time limitation was applied in this review and both in vitro and in vivo studies were included. Firstly, we will give a brief explanation of each selected orphan GPCR and will then discuss its role in the pathophysiology of MS.
    Orphan GPCRs and multiple sclerosis
    Conclusion Our knowledge regarding the physiological role of orphan GPCRs is very limited. However, various studies show that this group of receptors has important roles in the pathophysiology of neurodegenerative disorders including MS. The present review unveiled the role of orphan GPCRs in the initiation and progression of MS. Some of these receptors including GPR30 and GPR97 have pro-myelination effects while some others have inhibitory actions on myelination, both in the peripheral and central nervous systems. Orphan GPCRs, via mechanisms other than myelination, may also affect MS including modulation of immune cell responses and cytokine release. For example, some of them were able to decrease INF-γ, TNF-α, IL-1β, IL-6, IL-12, IL-17, and IL-23 and some were able to affect T helper cell function. In addition, GPR50 increased neurite length and filopodia- and lamellipodia-like structures implying that some of these receptors may even change the structure of the neurons. Involvement of GPR37 and GPR109 in the therapeutic effects of fingolimod and dimethyl fumarate, as two oral medications for the treatment of MS, even further highlights the therapeutic potentials of these receptors in the treatment of MS. As mentioned, orphan GPCRs are involved in the modulation of various neurological and psychological disorders [9,10]. It is well known that patients with MS have various concomitant diseases including anxiety, depression, psychosis, and pain [86,87]. Considering these findings, it may be suggested that these receptors can be targeted for the treatment of MS and concomitant diseases. However, many more studies are needed for this aim.
    Conflicts of interest
    Acknowledgment This study was partially supported by the Research Council of Mashhad University of Medical Sciences, Mashhad, Iran.
    Microglia surround the amyloid plaques that form in the brains of patients with Alzheimer's disease (AD), but their role is controversial. Under inflammatory conditions, these cells can express GPR84, an orphan receptor whose pathophysiological role is unknown. Here, we report that GPR84 is upregulated in microglia of APP/PS1 transgenic mice, a model of AD. Without GPR84, these mice display both accelerated cognitive decline and a reduced number of microglia, especially in areas surrounding plaques. The lack of GPR84 affects neither plaque formation nor hippocampal neurogenesis, but promotes dendritic degeneration. Furthermore, GPR84 does not influence the clinical progression of other diseases in which its expression has been reported, , experimental autoimmune encephalomyelitis (EAE) and endotoxic shock. We conclude that GPR84 plays a beneficial role in amyloid pathology by acting as a sensor for a yet unknown ligand that promotes microglia recruitment, a response affecting dendritic degeneration and required to prevent further cognitive decline.