TRPV4 activation triggers the release of melatonin from human non-pigmented ciliary epithelial cells

Alkozi, Hanan Awad; Pintor, Jesús

doi:10.1016/j.exer.2015.04.019

Cited by 24 publications

(28 citation statements)

References 17 publications

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“…It has been suggested that TRPV4 channels in anterior eye tissues such as the CB and/or trabecular meshwork might regulate IOP (18,36). Specifically, if TRPV4 channels control the "inflow" pathway by regulating steady-state release of aqueous fluid then activation, suppression, or ablation of the channel might be expected to affect steady-state IOP.…”

Section: Trpv4 Signaling In Npe Cells Requires Activation Of the Canomentioning

confidence: 99%

“…2+ homeostasis in CB cells by focusing on TRPV4, a nonselective cation channel that was originally identified by its sensitivity to hypotonic challenge (8,17) but was also recently suggested to regulate melatonin release from the CB (18). Immunocytochemistry with a validated antibody (19,20), showed clear TRPV4 immunoreactivity (ir) across the mouse CB.…”

Section: Camentioning

confidence: 99%

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Differential volume regulation and calcium signaling in two ciliary body cell types is subserved by TRPV4 channels

Lakk

Frye

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Fluid secretion by the ciliary body plays a critical and irreplaceable function in vertebrate vision by providing nutritive support to the cornea and lens, and by maintaining intraocular pressure. Here, we identify TRPV4 (transient receptor potential vanilloid isoform 4) channels as key osmosensors in nonpigmented epithelial (NPE) TRPV4 | ciliary body | intraocular pressure | aqueous humor | glaucoma F ormation of aqueous humor in the vertebrate eye takes place within the ciliary body (CB), a highly folded tissue consisting of pigmented epithelial (PE) cells, nonpigmented epithelial (NPE) cells, and the ciliary muscle (1, 2). Together, PE cells, which face the vascularized stroma and represent a forward continuation of the retinal pigment epithelium (RPE), and NPE cells, which face the posterior chamber (lumen) of the eye and extend the neuronal retina, form the blood-aqueous barrier and regulate the production and secretion of aqueous humor. The aqueous fluid supplies nutrients and oxygen to nonvascularized tissues (lens, cornea, and trabecular meshwork) and is ultimately drained through the ciliary muscle and the trabecular meshwork in the anterior chamber of the eye. Aqueous secretion is subserved by the unidirectional transport of ions and water through gap junctions between PE cells and NPE cells (3,4) and is driven by the osmotic gradient generated by Na + /K + exchange across basolateral NPE membranes (2-5). Despite the critical dependence of aqueous humor secretion on osmotic pressure (1, 4, 6), the molecular mechanism through which NPE and PE cells sense and regulate changes in volume is not well understood.In addition to osmotic shifts, CB cells experience mechanical forces associated with mean and time-varying aspects of intraocular pressure (IOP), a phenomenon that reflects balanced regulation of fluid secretion from NPE cells and its drainage from the anterior eye. Excessive IOP elevations represent the primary, and major, risk factor for contracting glaucoma (6, 7), an optic neuropathy that represents the second leading cause of blindness in the world. Therefore, aqueous secretion is often targeted by antiglaucoma medications that include β-adrenergic receptor antagonists, carbonic anhydrase inhibitors, α 2 -adrenergic agonists, and muscarinic cholinergic agonists (7). A key question, however, is whether CB cells themselves are able to sense force mediated by membrane stretch induced by hydrostatic pressure or swelling, and what such mechanisms might be.Here, we identify a key osmosensor in CB as transient receptor potential channel vanilloid isoform 4 (TRPV4), a polymodal nonselective cation-permeable channel that has been implicated in mechanotransduction (8, 9) as well as regulation of paracellular permeability in multiple epithelial tissues (10-15). Intriguingly, we found that TRPV4 is selectively distributed across CB by being confined to the NPE and excluded from PE cells. We characterized the functional role of TRPV4 as the predominant NPE swelling sensor and determined its contribution to...

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Section: Trpv4 Signaling In Npe Cells Requires Activation Of the Canomentioning

confidence: 99%

Section: Camentioning

confidence: 99%

Differential volume regulation and calcium signaling in two ciliary body cell types is subserved by TRPV4 channels

Lakk

Frye

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Measurements were performed in one eye of each patient, selected randomly. The collected samples were placed in an aqueous solution for further individual analysis by following the procedure described by Alkozi and Pintor 9 . Statistical data analysis was performed by the IBM SPSS programme (IBM SPSS Statistics for Windows, Version 23.0.…”

mentioning

confidence: 99%

“…It can be speculated that the activation of a TRPV4 channel, a membrane protein present in the ciliary processes, increases the secretion of extracellular melatonin to the aqueous humour, thus regulating intraocular pressure 9 . Nevertheless, since the results show a circadian pattern, the presence of melatonin in tears might also be regulated by the same mechanisms as the ones that control pineal gland physiology 10 …”

mentioning

confidence: 99%

Presence of melatonin in human tears

Carracedo

Carpena

Concepción

et al. 2017

Journal of Optometry

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“…A key point in the release of nucleotides to the aqueous humour is the TRPV4 channel described as ciliary body epithelial cells which indeed mediates in the release of different substances to the aqueous humour (Alkozi and Pintor, 2015). In this sense, either by producing osmotic changes, which is one of the main features of this TRPV channel, or by using selective agonists such as GSK1016790a, it has been seen that the amount of diadenosine tetraphosphate almost triplicates its extracellular concentration .…”

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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TRPV4 activation triggers the release of melatonin from human non-pigmented ciliary epithelial cells

Cited by 24 publications

References 17 publications

Differential volume regulation and calcium signaling in two ciliary body cell types is subserved by TRPV4 channels

Differential volume regulation and calcium signaling in two ciliary body cell types is subserved by TRPV4 channels

Presence of melatonin in human tears

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

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