Research: GPR30 an new target for remyelination

Epub: Hirahara Y, Matsuda KI, Yamada H, Saitou A, Morisaki S, Takanami K, Boggs JM, Kawata M G protein-coupled receptor 30 contributes to improved remyelination after cuprizone-induced demyelination. Glia. 2012 De. doi: 10.1002/glia.22445. 

Oestrogen exerts neuroprotective and promyelinating actions. The therapeutic effect has been shown in animal models of multiple sclerosis, in which the myelin sheath is specifically destroyed in the central nervous system. However, it remains unproven whether oestrogen is directly involved in remyelination via the myelin producing cells, oligodendrocytes, or which oestrogen receptors are involved. In this study, we found that the membrane-associated oestrogen receptor, the G protein-coupled receptor 30 (GPR30), also known as GPER, was expressed in oligodendrocytes in rat spinal cord and corpus callosum. Moreover, GPR30 was expressed throughout oligodendrocyte differentiation and promyelinating stages in primary oligodendrocyte cultures derived from rat spinal cords and brains. To evaluate the role of signalling via GPR30 in promyelination, a specific agonist for GPR30, G1, was administered to a rat model of demyelination induced by cuprizone treatment. Histological examination of the corpus callosum with oligodendrocyte differentiation stage-specific markers showed that G1 enhanced oligodendrocyte maturation in corpus callosum of cuprizone-treated animals. It also enhanced oligodendrocyte ensheathment of dorsal root ganglion (DRG) neurons in co-culture and myelination in cuprizone-treated animals. This study is the first evidence that GPR30 signaling promotes remyelination by oligodendrocytes after demyelination. GPR30 ligands may provide a novel therapy for the treatment of multiple sclerosis. 

G protein-coupled estrogen receptor 1 (GPER) also known as the G protein-coupled receptor 30 (GPR30) is a G protein-coupled receptor that in humans is encoded by the GPER gene.The protein binds oestrogen, resulting in intracellular calcium mobilization and synthesis of phosphatidylinositol (3,4,5)-trisphosphate in the nucleus. This protein therefore plays a role in the rapid non-genomic signalling events widely observed following stimulation of cells and tissues with oestrogen. This study demonstrates yet another target for the promotion of remyelination. It also seems that GPR30 can contribute to the protective influences of vitamin D₃.

So now we a building up a real big portfolio of myelin repair agents. These are some way off the clinic the big question is when will trials start will a single entity work or is it going to need a cocktail as it seems improbable that nature would create so many promyelinating targets if they were not somehow involved in a sequential process. Therefore what are the master regulators and will they just be involved in myelin repair? To date most targets have other functions which means potential side effects of developed drugs.

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