Activity of diadenosine polyphosphates at P2Y receptors stably expressed in 1321N1 cells

Glaucoma is a neurodegenerative disease that produces blindness. The main factor associated with this disease is an abnormally elevated intraocular pressure (IOP). To date, some attempts have been made to demonstrate the role of nucleotides modulating IOP, but never in a model of glaucoma. The DBA/2J mouse is an animal that develops the pathology spontaneously, starting from the typical rise in IOP at 9 months of age. Using this animal model, together with a control mouse, C57BL/6J, it has been possible to monitor the elevation in IOP in the glaucomatous mice and to check the ability of the dinucleotide diadenosine tetraphosphate AKA Ap 4 A to reduce IOP. The topical application of Ap 4 A when IOP is maximal (9-12 months) reduced IOP 30.6 ± 6.6% in the DBA/2J and 17.9 ± 4.0% in the C57BL/ 6J mice. Concentration response curves in both animal strains produced similar pD2 values; these being 4.9 ± 0.5 and 5.1 ± 0.4 for the normotensive C57BL/6J and the glaucomatous DBA/2J respectively. Antagonist studies showed differences between the control and the glaucomatous animals. In particular, the main receptor reducing IOP in the control animal was the P2Y 1 receptor and in the glaucomatous model the P2Y 6 , although the participation of other P2 receptors cannot be ruled out. The long-term effect of Ap 4 A applied three times a week for 3 months showed a clear stop in the elevation of IOP in the glaucomatous model, thus indicating the possibility of using Ap 4 A as an effective compound for the treatment of glaucoma.

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“…Ap 4 A has been described as P2Y 1 , P2Y 2 and P2Y 6 selective agonist and P2Y 13 selective antagonist [19][20][21][22]. *** *** Fig.…”

Section: Antagonist Studiesmentioning

confidence: 99%

Diadenosine tetraphosphate as a potential therapeutic nucleotide to treat glaucoma

Fonseca

Martínez-Águila

Lara

et al. 2016

Purinergic Signalling

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“…Regarding the P2Y receptors, P2Y 1 and P2Y 2 are the ones that are stimulated by diadenosine polyphosphates (Patel et al, 2001). The tandem Ap 4 A-P2Y 2 is of special interest since it participates in many physiological processes in many ocular structures ( Fig.…”

Section: Purinergic Receptors and Dinucleoside Polyphosphatesmentioning

confidence: 99%

The role of dinucleoside polyphosphates on the ocular surface and other eye structures

Carracedo

Crooke

Guzmán-Aránguez

et al. 2016

Progress in Retinal and Eye Research

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a b s t r a c tDinucleoside polyphosphates comprises a group of dinucleotides formed by two nucleosides linked by a variable number of phosphates, abbreviated NpnN (where n represents the number of phosphates). These compounds are naturally occurring substances present in tears, aqueous humour and in the retina. As the consequence of their presence, these dinucleotides contribute to many ocular physiological processes. On the ocular surface, dinucleoside polyphosphates can stimulate tear secretion, mucin release from goblet cells and they help epithelial wound healing by accelerating cell migration rate. These dinucleotides can also stimulate the presence of proteins known to protect the ocular surface against microorganisms, such as lysozyme and lactoferrin. One of the latest discoveries is the ability of some dinucleotides to facilitate the paracellular way on the cornea, therefore allowing the delivery of compounds, such as antiglaucomatous ones, more easily within the eye. The compound Ap 4 A has been described being abnormally elevated in patient's tears suffering of dry eye, Sjogren syndrome, congenital aniridia, or after refractive surgery, suggesting this molecule as biomarker for dry eye condition. At the intraocular level, some diadenosine polyphosphates are abnormally elevated in glaucoma patients, and this can be related to the stimulation of a P2Y 2 receptor that increases the chloride efflux and water movement in the ciliary epithelium. In the retina, the dinucleotide dCp 4 U, has been proven to be useful to help in the recovery of retinal detachments. Altogether, dinucleoside polyphosphates are a group of compounds which present relevant physiological actions but which also can perform promising therapeutic benefits.

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“…Data were normalized for loading efficiency and the peak height of the response was determined. Nucleotide analogs were prepared as described in [13]. Where indicated, 10 mM stocks of ADP and UDP were treated with hexokinase (15 U/ml) in the presence of glucose for 90 min to remove contaminating triphosphates.…”

Section: Activity Measurementsmentioning

confidence: 99%

“…To determine whether this is also true of Xenopus P2Y 11 this receptor was expressed in 1321N1 human astrocytoma cells, which do not respond to extracellular nucleotides [12,13]. Several different nucleotide analogs including ATPcS, the most potent agonist at the human P2Y 11 receptor [14], elicit a functional response in both assays ( Fig.…”

Section: Functional Properties Of the X Laevis P2y 11mentioning

confidence: 99%

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A novel nucleotide receptor in Xenopus activates the cAMP second messenger pathway

Devader¹,

Drew²,

Geach³

et al. 2007

FEBS Letters

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We describe a Xenopus P2Y receptor that shares only weak homology with members of the mammalian P2Y family, being most similar to human P2Y 11 . When activated by nucleotide analogs, it stimulates both calcium and cAMP mobilization pathways, a feature unique, among mammalian P2Y receptors, to P2Y 11 . Activity can be blocked by compounds known to act as antagonists of mammalian P2Y 11 . Genomic synteny between Xenopus and mammals suggests that the novel gene is a true ortholog of P2Y 11 . Xenopus P2Y 11 is transcribed during embryonic development, beginning at gastrulation, and is enriched in the developing nervous system.

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Activity of diadenosine polyphosphates at P2Y receptors stably expressed in 1321N1 cells

Cited by 57 publications

References 27 publications

Diadenosine tetraphosphate as a potential therapeutic nucleotide to treat glaucoma

Diadenosine tetraphosphate as a potential therapeutic nucleotide to treat glaucoma

The role of dinucleoside polyphosphates on the ocular surface and other eye structures

A novel nucleotide receptor in Xenopus activates the cAMP second messenger pathway

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