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Raphael Rouget, Melanie Sanchez, David Hamel, François Duhamel, Mathieu Nadeau-Vallée, Tang Zhu, Carlos Rivera, Nicholas Sitaras, Przemyslaw Sapieha, Sylvain Chemtob; The succinate receptor GPR91 signals from the Endoplasmic Reticulum. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):58.
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© ARVO (1962-2015); The Authors (2016-present)
Retinopathy of prematurity (ROP) is a common cause of visual loss in childhood leading to lifelong vision impairment and blindness. In response to elevated oxygen, the normal demand is suppressed and ROP develops in the premature child resulting in arrest of vascular development and degeneration of blood vessels. Consequently, an abundant retinal neovascularization penetrates the vitreous, predisposing to retinal detachment. We have identified the crucial role of succinate receptor GPR91 in the retinal vascular development and its detrimental effect in oxygen-induced retinopathy (OIR). During vascular compromise in the neuronal retina, succinate levels increase inducing an angiogenic response via GPR91.This indicates that the interplay between succinate and GPR91 could be a major part of the mechanism by which neurons sense hypoxic stress leading to energy deficit, which triggers vessel growth.
Initial localization of GPR91 in RGCs showed an intracellular distribution unlike its plasma membrane (PM) location in the kidneys. In fact, increase in mRNA of pro-angiogenic factors, following succinate stimulation, was downregulated in the presence of transporter inhibitor pointing to a functional intracellular GPR91.We investigated which mechanism retain GPR91 intracellular and if the location results in cellular changes distinct from those triggered by PM GPR91 stimulation. Confocal and electron microscopy in cultured cells showed that GPR91 colocalized with endoplasmic reticulum (ER) confirming its intracellular localization. Subsequently, we have found a conserved glycosylation site which when mutated leads to PM trafficking of the receptor (mutGPR91). Co-immunoprecipitation of ER-bound GPR91 vs mutGPR91 confirmed that only intracellular GPR91 interacted with ER.
The cellular location of GPR91 shows a critical role on its activity. Intracellular GPR91 activates the MAPK and AKT signaling pathways following succinate treatment, however mutGPR91, only activated the MAPK pathway. In addition, only intracellular GPR91 can increase the expression of VEGFA. In turn, mutGPR91, in the presence of succinate, induced a stronger expression of pro-angiogenic factors, indicating that cellular location controls how GPR91 responds to its ligand.
Therapeutic options for proliferative retinopathies are still limited to antagonists of VEGF. GPR91 offers an alternative target in post-ischemia revascularization.
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