Biological insights from the direct measurement of purine release

Dale, Nicholas

doi:10.1016/j.bcp.2021.114416

Cited by 18 publications

(10 citation statements)

References 149 publications

(210 reference statements)

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“…This apparent discrepancy can be explained by the existence of alternative pathways which ensure local ADO supply to the retinal vessels. These mechanisms might particularly include the direct release of endogenous ADO by vascular and neuronal cells via bidirectional equilibrative nucleoside transporters [ 29 , 53 ], ADO formation at the vitreoretinal interface through soluble intravitreal CD73 activity [ 16 , 23 ], as well as metabolism of AMP into ADO by neighboring CD73 + microglial cells located in close vicinity to the vessel wall (current study).…”

Section: Discussionmentioning

confidence: 99%

CD73 controls ocular adenosine levels and protects retina from light-induced phototoxicity

Losenkova

Ragauskas²,

Cerrada-Gimenez

et al. 2022

Cell. Mol. Life Sci.

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ATP and adenosine have emerged as important signaling molecules involved in vascular remodeling, retinal functioning and neurovascular coupling in the mammalian eye. However, little is known about the regulatory mechanisms of purinergic signaling in the eye. Here, we used three-dimensional multiplexed imaging, in situ enzyme histochemistry, flow cytometric analysis, and single cell transcriptomics to characterize the whole pattern of purine metabolism in mouse and human eyes. This study identified ecto-nucleoside triphosphate diphosphohydrolase-1 (NTPDase1/CD39), NTPDase2, and ecto-5′-nucleotidase/CD73 as major ocular ecto-nucleotidases, which are selectively expressed in the photoreceptor layer (CD73), optic nerve head, retinal vasculature and microglia (CD39), as well as in neuronal processes and cornea (CD39, NTPDase2). Specifically, microglial cells can create a spatially arranged network in the retinal parenchyma by extending and retracting their branched CD39high/CD73low processes and forming local “purinergic junctions” with CD39low/CD73− neuronal cell bodies and CD39high/CD73− retinal blood vessels. The relevance of the CD73–adenosine pathway was confirmed by flash electroretinography showing that pharmacological inhibition of adenosine production by injection of highly selective CD73 inhibitor PSB-12489 in the vitreous cavity of dark-adapted mouse eyes rendered the animals hypersensitive to prolonged bright light, manifested as decreased a-wave and b-wave amplitudes. The impaired electrical responses of retinal cells in PSB-12489-treated mice were not accompanied by decrease in total thickness of the retina or death of photoreceptors and retinal ganglion cells. Our study thus defines ocular adenosine metabolism as a complex and spatially integrated network and further characterizes the critical role of CD73 in maintaining the functional activity of retinal cells.

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Section: Discussionmentioning

confidence: 99%

CD73 controls ocular adenosine levels and protects retina from light-induced phototoxicity

Losenkova

Ragauskas²,

Cerrada-Gimenez

et al. 2022

Cell. Mol. Life Sci.

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“…This apparent discrepancy can be explained by the existence of alternative pathways which ensure local ADO supply to the retinal vessels. These mechanisms might particularly include the direct release of endogenous ADO by vascular and neuronal cells via equilibrative nucleoside transporters [27,50], metabolism of AMP into ADO by neighboring CD73 + cells located in close vicinity to the vessel wall (such as microglia and horizontal cells; current study), as well as ADO formation at the vitreoretinal interface through soluble intravitreal CD73 activity [16,21].…”

Section: Discussionmentioning

confidence: 99%

CD73 Controls Ocular Adenosine Levels and Protects Retina from Light-Induced Phototoxicity

Losenkova

Takeda

Ragauskas³

et al. 2021

Preprint

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Ocular ATP and adenosine have emerged as important signalling molecules involved in vascular remodeling, retinal functioning and neurovascular coupling in the mammalian eye. However, little is known about the regulatory mechanisms of purinergic signaling in the eye. Here, we used three-dimensional multiplexed imaging in combination with in situ enzyme histochemistry, flow cytometric analysis and single cell transcriptomics to characterize the pattern of purine metabolism in the mouse and human eyes. This study identified NTPDase1/CD39 and ecto-5’-nucleotidase/CD73 as major ecto-nucleotidases, which are selectively expressed in the optic nerve head, vascular endothelial and perivascular cells, outer segments of photoreceptors, retinal microglia, and cornea and coordinately control ATP and adenosine levels. The relevance of the CD73-adenosine axis was confirmed by flash electroretinography showing that pharmacological inhibition of CD73 in dark-adapted mouse eyes rendered the animals hypersensitive to prolonged bright light, manifested as decreased a-wave and b-wave amplitudes and a loss of retinal ganglion cells. Our study thus defines ocular adenosine metabolism as a complex and spatially integrated network and characterizes its critical role in protecting the retina from light-induced phototoxicity.

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“…It is important to note that the distance over which ATP can diffuse will depend on expression and distribution of ectoATPases. Simulations based on realistic assumptions suggest that ectoATPases will limit ATP diffusion to a radius of only ~10 μm, whereas ADP (which can activate subtypes of P2Y receptors) can diffuse much further, 10-100 of μm (Dale, 2021a).…”

Section: Two Functional Modes Of Channel Mediated Atp Releasementioning

confidence: 99%