Evidence for Multiple P2Y Receptors in Trabecular Meshwork Cells

Crosson, Craig E.; Yates, Phillip W.; Bhat, Aruna N.; Mukhin, Y.; Husain, Shahid

doi:10.1124/jpet.103.060319

Cited by 17 publications

(15 citation statements)

References 27 publications

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“…Using the same antibodies, it was possible to identify these receptors in rat ocular structures such as the corneal epithelium (P2Y 6 ) and the retinal pigmented epithelium (P2Y 11 ) and to confirm the existence of P2Y 1 and P2Y 2 in sections containing the TM (Pintor et al, 2004). Other studies have also reported the presence of P2Y 1 and P2Y 2 receptors in bovine TM cells (Cui et al, 2001) and P2Y 1 , P2Y 4 , and P2Y 11 in a human TM cell line (Crosson et al, 2004). Ap n As are known to activate several different purinergic receptors: Ap 3 A and Ap 4 A both activate P2Y 1 receptors with different selectivity, whereas Ap 5 A is, in general, less effective at this receptor (Schachter et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…2 and 3) (Crosson et al, 2004;Soto et al, 2004), bradykinin (Llobet et al, 1999), and carbachol (Shade et al, 1996). Interestingly, drugs that induce large and sustained Ca 2ϩ mobilizations either decrease outflow facility (bradykinin, carbachol, and endothelin-1) (Wiederholt et al, 1995;Llobet et al, 1999) or do not modify it (Up 4 U and ATP; this study and D. Soto and X. Gasull, unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

“…In the eye, P2Y receptors have been found in different tissues, including retina, ciliary body, cornea, conjunctiva, choroids, and optic nerve head (Cowlen et al, 2003;Pintor et al, 2003b). Moreover, it is known that TM cells release ATP upon stimulation with hypotonic stimuli (Cui et al, 2001;Fleischhauer et al, 2003;Soto et al, 2004) or shear stress (Cui et al, 2001), and recently the presence of purinergic P2Y receptors has also been found in a human TM cell line (Crosson et al, 2004). However, a detailed study of the effects of purinergic receptor activation on outflow facility has yet to be conducted.…”

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confidence: 99%

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Effects of Dinucleoside Polyphosphates on Trabecular Meshwork Cells and Aqueous Humor Outflow Facility

Soto¹,

Pintor²,

Peral³

et al. 2005

J Pharmacol Exp Ther

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The most important risk factor for the development of glaucoma is elevated intraocular pressure (IOP). Hypotensive drugs decrease IOP, preventing optic nerve damage and further vision loss. The balance between aqueous humor (AH) production and drainage determines IOP, and problems in AH outflow pathways are associated with open-angle glaucoma development. Previous studies have shown the presence of diadenosine tetraphosphate (Ap 4 A) and pentaphosphate (Ap 5 A) in the AH. Topic application of Ap 4 A to the cornea decreased IOP, whereas Ap 5 A increased it. Because dinucleoside polyphosphates stimulate P2Y purinergic receptors, we studied their presence in trabecular meshwork (TM) cells. Additionally, the effects of diadenosine polyphosphates (Ap n As; n ϭ 3-5) and Up 4 U (P 1 ,P 4 -(diuridine 5Ј)-tetraphosphate; INS365) in outflow facility were tested. P2Y 1 , P2Y 2 , and P2Y 4 receptors were detected in TM cells by Western blot and immunocytochemistry. In TM cells, Ap 3 A, Ap 4 A, and Ap 5 A induced discrete intracellular calcium concentration ([Ca 2ϩ ] i ) mobilizations compared with higher and more sustained [Ca 2ϩ ] i mobilizations after Up 4 U application. In bovine ocular anterior segments perfused at constant pressure, 1 M Ap 3 A or Ap 4 A increased outflow facility, whereas Up 4 U or Ap 5 A did not modify it. 2-MeSADP, a selective P2Y 1 agonist, induced outflow facility increases similar to those obtained after Ap 3 A and Ap 4 A, and these were prevented by addition of the selective P2Y 1 receptor antagonist MRS-2179 (2Ј-deoxy-N 6 -methyladenosine-3Ј,5Ј-diphosphate). Our results demonstrate that the hypotensive effect of Ap 4 A and other dinucleotides is mediated, at least in part, by increasing trabecular outflow facility through activation of P2Y 1 receptors. The latter would seem to be an interesting target in the development of antiglaucomatous drugs to selectively increase AH outflow.In the eye, elevated intraocular pressure (IOP) due to impaired aqueous humor (AH) drainage is a major risk factor in the development of glaucoma. Glaucoma is the most important cause of irreversible nontraumatic blindness in the world and affects more than 66 million people. The main determinant of IOP is the volume of AH contained in the anterior and posterior chambers. AH is produced in the ciliary epithelium and eliminated through the outflow pathways in the anterior chamber angle. In several species, but especially in the primate eye, most AH flows through the trabecular meshwork (TM), a sponge-like filtering tissue, where it reaches Schlemm's canal and the collector channels before finally entering the venous system. The structure of the TM and its ability to modify its resistance to AH outflow play a key role in maintaining the IOP in the anterior chamber within its physiological range. TM cells express several receptors to substances released either in the AH from different ocular tissues (Mitchell et al., 1998;Coca-Prados et al., 1999) or from ocular innervation (Selbach et al., 2000) in physiologic...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Effects of Dinucleoside Polyphosphates on Trabecular Meshwork Cells and Aqueous Humor Outflow Facility

Soto¹,

Pintor²,

Peral³

et al. 2005

J Pharmacol Exp Ther

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“…mRNA, protein, and functional evidence have been found for purinergic receptors P2Y 1 , P2Y 2 , P2Y 4 , and P2Y 11 in the bovine trabecular meshwork (Figure 1) [101, 102] and in the human HTM-3 cell line [103]. Depending on the purinergic receptor activated, an increase or decrease in aqueous humor outflow is found.…”

Section: Ocular Sensory Innervation and Purinergic Receptors P2 Inmentioning

confidence: 99%

Purinergic Receptors in Ocular Inflammation

Guzmán-Aránguez

Gasull

Diebold

et al. 2014

Mediators of Inflammation

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Inflammation is a complex process that implies the interaction between cells and molecular mediators, which, when not properly “tuned,” can lead to disease. When inflammation affects the eye, it can produce severe disorders affecting the superficial and internal parts of the visual organ. The nucleoside adenosine and nucleotides including adenine mononucleotides like ADP and ATP and dinucleotides such as P1,P4-diadenosine tetraphosphate (Ap4A), and P1,P5-diadenosine pentaphosphate (Ap5A) are present in different ocular locations and therefore they may contribute/modulate inflammatory processes. Adenosine receptors, in particular A2A adenosine receptors, present anti-inflammatory action in acute and chronic retinal inflammation. Regarding the A3 receptor, selective agonists like N6-(3-iodobenzyl)-5′-N-methylcarboxamidoadenosine (CF101) have been used for the treatment of inflammatory ophthalmic diseases such as dry eye and uveoretinitis. Sideways, diverse stimuli (sensory stimulation, large intraocular pressure increases) can produce a release of ATP from ocular sensory innervation or after injury to ocular tissues. Then, ATP will activate purinergic P2 receptors present in sensory nerve endings, the iris, the ciliary body, or other tissues surrounding the anterior chamber of the eye to produce uveitis/endophthalmitis. In summary, adenosine and nucleotides can activate receptors in ocular structures susceptible to suffer from inflammatory processes. This involvement suggests the possible use of purinergic agonists and antagonists as therapeutic targets for ocular inflammation.

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“…Effect on the trabecular meshwork. Trabecular meshwork presents many P2Y receptors, mainly P2Y 1 , P2Y 2 , and P2Y 4 in bovine TM cells (Soto et al, 2005) and P2Y 11 in a cellular line of human trabecular meshwork (Crosson et al, 2004). Diadenosine polyphosphates do not activate all these receptors in the same way.…”

Section: Presence In the Aqueous Humourmentioning

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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Evidence for Multiple P2Y Receptors in Trabecular Meshwork Cells

Cited by 17 publications

References 27 publications

Effects of Dinucleoside Polyphosphates on Trabecular Meshwork Cells and Aqueous Humor Outflow Facility

Effects of Dinucleoside Polyphosphates on Trabecular Meshwork Cells and Aqueous Humor Outflow Facility

Purinergic Receptors in Ocular Inflammation

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

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