Purinergic transmission in the retina (original) (raw)
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Purinergic signaling in the retina: From development to disease
Brain Research Bulletin, 2018
Retinal injuries and diseases are major causes of human disability involving vision impairment by the progressive and permanent loss of retinal neurons. During development, assembly of this tissue entails a successive and overlapping, signal-regulated engagement of complex events that include proliferation of progenitors, neurogenesis, cell death, neurochemical differentiation and synaptogenesis. During retinal damage, several of these events are reactivated with both protective and detrimental consequences. Purines and pyrimidines, along with their metabolites are emerging as important molecules regulating both retinal development and the tissue's responses to damage. The present review provides an overview of the purinergic signaling in the developing and injured retina. Recent findings on the presence of vesicular and channel-mediated ATP release by retinal and retinal pigment epithelial cells, adenosine synthesis and release, expression of receptors and intracellular signaling pathways activated by purinergic signaling in retinal cells are reported. The pathways by which purinergic receptors modulate retinal cell proliferation, migration and death of retinal cells during development and injury are summarized. The contribution of nucleotides to the self-repair of the injured zebrafish retina is also discussed.
Expression of purinergic receptors in bipolar cells of the rat retina
Molecular Brain Research, 2000
P2X receptors are ligand-gated ion channels which are activated by excitatory neurotransmitter ATP. Despite considerable evidence of signaling by extracellular nucleotides in other sensory systems, P2X receptors in the visual system have only rarely been studied, and almost nothing is known about their functional significance in the retina. To determine whether ATP plays a role in the modulation of vertical retinal signal pathways, we examined the expression of P2X receptor mRNA in freshly isolated bipolar cells of the rat retina Ž. Brown Norway, P25 using the single-cell RT-PCR technique. Positive amplification signals were found in about 33% of the bipolar cells for P2X , P2X and P2X but not for P2X mRNA. We conclude that at least a subpopulation of bipolar cells in the rat retina 3 4 5 7 expresses ionotropic P2 receptors of the P2X type and that these possibly exert a neuromodulatory influence on information processing in the retina.
Experimental Eye Research, 2014
This review highlights recent findings describing how purines modulate physiological and pathophysiological responses of ocular tissues. For example, in lacrimal glands the cross-talk between P2X7 receptors and both M3 muscarinic receptors and α1D-adrenergic receptors can influence secretion. In the cornea, purines lead to post-translational modification of EGFR and structural proteins that participate in wound repair in the epithelium and influence the expression of matrix proteins in the stroma. Purines act at receptors on both the trabecular meshwork and ciliary epithelium to regulate intraocular pressure (IOP); ATP-release pathways of inflow and outflow cells differ, possibly permitting differential modulation of adenosine delivery. Regulators of TM-cell ATP release include cell volume, stretch, extracellular Ca 2+ concentration, oxidation state, actin remodeling and possibly endogenous cardiotonic steroids. In the lens, osmotic stress leads to ATP release following TRPV4 activation upstream of hemichannel opening. In the anterior eye, diadenosine polyphosphates such as Ap4A act at P2 receptors to modulate the rate and composition of tear secretion, impact corneal wound healing and lower IOP. In the retina, the Gq11-coupled P2Y1-receptor contributes to volume control in Müller cells and thus the retina. P2X receptors are expressed in neurons in the inner and outer retina and contribute to visual processing as well as the demise of RGCs. In RPE cells, the balance between extracellular ATP and adenosine may modulate lysosomal pH and the rate of lipofuscin formation. In optic nerve head astrocytes, mechanosensitive ATP release via pannexin hemichannels, coupled with stretch-dependent upregulation of pannexins, provides a mechanism for ATP signaling in chronic glaucoma. With so many receptors linked to divergent functions throughout the eye, ensuring the transmitters remain local and stimulation is restricted to the intended target may be a key issue in understanding how physiological signaling becomes pathological in ocular disease.
The Journal of Physiology, 1999
The retinal pigment epithelium (RPE) carries out a number of roles that are essential for the maintenance and viability of the neurosensory retina. These roles include phagocytosis of shed rod and cone outer segments, melanin synthesis and recycling and regulation of subretinal volume via ioncoupled fluid absorption (Steinberg & Miller, 1979; Zinn & Benjamin-Henkind, 1979; Clark, 1986). In order to carry out these diverse functions, the RPE must be able to detect and respond to paracrine signals coming from the adjacent choroidal andÏor neural retinal tissue andÏor via systemic sources. A number of metabotropic receptors have been identified on the RPE including those for dopamine, acetylcholine, adrenaline (epinephrine) and adenosine (Friedman et al. 1988; Dearry et al. 1990; Frambach et al. 1990). Activation of these receptors by their respective signalling molecules has been linked to changes in light-evoked responses (Dearry et al. 1990; Gallemore & Steinberg, 1990), phagocytic ability (Gregory et al. 1994) and ion and fluid transport across the RPE (Edelman & Miller, 1991; Joseph & Miller, 1992). Recently, in monolayers of bovine and rat RPE, extracellular adenosine 5'-triphosphate (ATP) and uridine triphosphate (UTP) were demonstrated to induce changes in intracellular Ca¥ and transepithelial ion and fluid movement (Stalmans & Himpens, 1997; Peterson et al. 1997). A role for intracellular ATP has also recently been demonstrated for the activation of a delayed inwardly rectifying K¤ current (IK(IR)) in isolated bovine RPE cells (Hughes & Takahira, 1998). These findings support the presence of metabotropic purinoceptors and suggest that ATP may act as an important paracrine signal in the RPE. Purinoceptors are divided into two main classes, P1 and P2, based on their selectivity for adenosine and ATP, respectively (Burnstock & Kennedy, 1985). Adenosine or P1
Evidence for the involvement of purinergic P2X 7 receptors in outer retinal processing
European Journal of Neuroscience, 2006
Extracellular ATP mediates fast excitatory neurotransmission in many regions of the central nervous system through activation of P2X receptors. Although several P2X receptor subunits have been identified in the mammalian retina, little is known about the functional role of these receptors in retinal signalling. The purpose of the present study was to investigate whether purinergic P2X 7 receptors are involved in outer retinal processing by assessing receptor localization, degradation of extracellular ATP and the effect of functional activation of P2X 7 receptors on the electroretinogram (ERG). Using light and electron microscopy, we demonstrated that P2X 7 receptors are expressed postsynaptically on horizontal cell processes as well as presynaptically on photoreceptor synaptic terminals in both the rat and marmoset retina. Using an enzyme cytochemical method, we showed that ecto-ATPases are active in the outer plexiform layer of the rat retina, providing a mechanism by which purinergic synaptic transmission can be rapidly terminated. Finally, we evaluated the role of P2X 7 receptors in retinal function by assessing changes to the ERG response of rats after intravitreal delivery of the P2X 7 receptor agonist benzoyl benzoyl ATP (BzATP). Intravitreal injection of BzATP resulted in a sustained increase (up to 58%) in the amplitude of the photoreceptor-derived a-wave of the ERG. In contrast, BzATP caused a transient reduction in the rod-and cone-derived postreceptoral responses. These results provide three lines of evidence for the involvement of extracellular purines in outer retinal processing.
Neurochemistry International, 1989
Rabbit retinae preloaded with [3H]adenosine were superfused in vitro and the effect of neurotransmitter agonists and antagonists on the release of [3H]purines was studied. Glutamic acid, aspartic acid, kainic acid (KA), quisqualic acid (QUIS) and N-methyl-D-aspartic acid (NMDA) all stimulated the efflux of [3H] labelled and endogenous purines. Their effect was reduced in a Ca2+-free medium except when using a high concentration (100 #M) of KA, QUIS and NMDA. The effect of aspartic acid and of NMDA were blocked by 2-amino-7-phosphono-heptanoic acid (APH) and 2-amino-5phosphono-valeric acid (APV). Carbachol also increased the release of adenosine-derived radioactivity and this effect was reduced by the removal of Ca 2÷ and by pretreatment with atropine. T-Aminobutyric acid (GABA) and muscimol, induced a small increase in the release which was Ca2+-dependent and was blocked by bicuculline and picrotoxin. Dopamine elicited an increase in the release which was partially reduced in a Ca2+-free medium and was blocked by haloperidol. Glycine and 5-hydroxytryptamine (5-HT) also induced small but significant increases. The neurotransmitter antagonists had an effect of their own. Superfusion with APH and APV depressed the outflow of radioactivity whereas bicuculline, picrotoxin, strychnine and haloperidol enhanced it. The K+-evoked release of [3H]purines was reduced by haloperidol and by 5-HT. The observations indicate that stimulation of several important neurotransmitter receptors in the retina elicits the release of adenosine derivatives. The results with the antagonists also suggest that purines are continuously released as a result of a tonic activation of the respective membrane receptors.
Purinergic signaling involved in Müller cell function in the mammalian retina
Progress in Retinal and Eye Research, 2011
Purines (in particular, ATP and adenosine) act as neuro- and gliotransmitters in the sensory retina where they are involved in bidirectional neuron-glia signaling. This review summarizes the present knowledge about the expression and functional importance of P1 (adenosine) and P2 (nucleotide) receptors in Müller glial cells of the mammalian retina. Mammalian Müller cells express various subtypes of adenosine receptors and
Purinergic signalling in sensory systems
Seminars in Neuroscience, 1996
Extracellular purines play multiple roles in a variety of sensory systems acting as neural signalling and humoral factors via purinoceptors. For example, ATP and adenosine have a neurosignalling role in autonomic sensory-motor reflexes, mechanoreception and chemoreception mediated via vagus nerve afferents, and in nociception. Purinergic neuromodulation of vision via adenosine in the retina is well established and there is mounting evidence for a neuromodulatory role for ATP in the inner ear. Humoral purinergic actions are found in the eye where adenosine clearly has an important vascular and humoral influence and in the inner ear where ATP probably regulates fluid homeostasis, hearing sensitivity and development. Clearly purinergic signalling underpins the physiology of many of the body's sensory systems.
Molecular Brain Research, 2000
P2X receptors are ligand-gated ion channels activated by ATP. They are expressed in a broad variety of tissues. To date, eight P2X Ž. receptor subunits P2X-P2X , P2XM have been cloned. In spite of the considerable evidence of signaling by extracellular nucleotides 1 7 in other sensory systems, only few studies have been undertaken in the retina. In earlier studies, we have demonstrated that there is mRNA expression of the P2X and P2X subunits in the rat retina. In the present study, molecular biological methods were used to 2-5 7 Ž. Ž. investigate expression of P2X receptor mRNA in freshly isolated Muller cells MCs of the adult rat retina Brown Norway. A total of 36 MCs was analyzed, employing the single-cell RT-PCR. A positive amplification signal of 11r14 for P2X-mRNA, 5r10 for 3 P2X-mRNA, 3r10 for P2X-mRNA and 0r8 for P2X-mRNA was revealed. Additionally, the astroglial identity of the cells under 4 5 7 Ž. studied was confirmed in 10 cases by simultaneous amplification of RT-PCR products of glutamine synthetase GS-and P2X-mRNA. We conclude that MCs of rat retina express ionotropic P2 receptors, which, in addition to other functions, may play a key role within the recently described long range calcium signaling and the fast direct glia-neuron interactions in the rat retina.
Measurement of purine nucleoside concentration in the intact rat retina
Journal of Neuroscience Methods, 1996
Adenosine, produced from the decomposition of adenosine triphosphate, is believed to provide protective effects during ischemia. On the other hand, adenosine metabolites may serve as precursors for oxygen free radical formation. These substances have not been previously measured in intact vertebrate retina, where adenosine and its metabolites may play a role in the pathogenesis of ischemic injury. The small tissue mass of the retina, particularly in rats, renders these measurements challenging. Furthermore, accurate measurement of purine nucleosides requires immediate cessation of ongoing adenosine metabolism. Concentrations of adenosine and its purine nucleoside metabolites inosine, hypoxanthine, and xanthine in the retina of ketamine/xylazine-anesthetized rats were measured after in situ freezing using high-performance liquid chromatography. The retina was removed from the frozen eyes and analyzed. Quantitative measurements were made possible through the use of an internal standard. Ischemia was induced by ligation of the central retinal artery. Retinal purine nucleoside concentrations did not differ between the two eyes of the rat under control conditions, and there was no effect of placement of the ligating suture itself compared to completely unmanipulated eyes. Use of two different in situ freezing methods yielded comparable results. To evaluate the impact of a period of ischemia, one retina of each rat was ischemlc for 30 min, and the other, non-ischemic. Our measurements were associated with a high degree of reproducibility and minimal variability, and significant changes in purine nucleoside concentrations were detectable in the retina after 30 min of ischemia. Our method may be used to assess the role of adenosine and its metabolites in the pathogenesis of ischemic neuronal injury, including in the retina.