The P2X7 Receptor in AMD

Review Article

Austin J Clin Ophthalmol. 2014;1(3): 1012.

The P2X7 Receptor in AMD

Dongli Yang1* and Jun Chen2

1Departments of Ophthalmology and Visual Sciences, University of Michigan, USA

2Departments of Internal Medicine, University of Michigan, USA

*Corresponding author: Dongli Yang, Department of Ophthalmology and Visual Sciences, University of Michigan, 344 Kellogg Eye Center, , 1000 Wall Street, Ann Arbor, MI 48105-5714, USA

Received: February 20, 2014; Accepted: February 24, 2014; Published: March 03, 2014

Abstract

Age–related macular degeneration (AMD) is the leading cause of blindness among people over the age of 50 worldwide. However, its exact causes and the underlying mechanisms remain largely unknown. The P2X7 receptor (P2X7R) is an ATP–gated cationic channel expressed in retina. Recent advances have highlighted the P2X7R–mediated pathophysiological processes in the development of AMD. This review will discuss the current literature regarding P2X7R in the RPE physiological and pathophysiological processes, and assess its potential impact with respect to AMD.

Keywords: AMD; apoptosis; P2X7; RPE.

Abbreviations

AMD: Age–related Macular Degeneration; ASC: Apoptosisassociated Speck–like protein containing a Caspase recruitment domain; ATP: Adenosine Triphosphate; BBG: Brilliant Blue G; BzATP: 2’3’–O–(4–benzoylbenzoyl)–ATP; CNV: Choroidal Neovascularization; IL–8: Interleukin 8; KN–62: 4– [(2S)–2– [(5–isoquinolinylsulfonyl) methylamino] –3 – oxo – 3 – ( 4 – phenyl – 1 –piperazinyl) propyl] phenyl isoquinolinesulfonic acid ester; MCP– 1: Monocyte Chemoattractant Protein–1; NF–?B: Nuclear Factor ?B; NLRP3: Nucleotide–binding domain and Leucine–Rich repeat containing family, Pyrin domain containing 3; oATP: Oxidized ATP; POSs: Photoreceptor Outer Segments; PPADS: Pyridoxal–Phosphate– 6–Azophenyl–,2’,4’–Disulphonic Acid; P2X7R: P2X7 Receptor; ROS: Reactive Oxygen Species; RPE: Retinal Pigmented Epithelium; Snps: Single Nucleotide Polymorphisms; VEGF: Vascular Endothelial Growth Factor

Introduction

Age–related macular degeneration (AMD) is the leading cause of blindness among people over the age of 50.It is a worldwide epidemic. In a cross–sectional study with 4 racial/ethnic groups aged 45–84 years, early AMD and late AMD were present in 4.0% and 0.5% of the cohort, respectively, varying from 2.4% and 0.2% in blacks, 3.8% and 0% in Hispanics, and 3.8% and 1.1% in Chinese to 6.0% and 0.5% in whites, respectively [1]. In a large retrospective longitudinal cohort study, among 2 259 061 individuals (whites, blacks, Latinos, and Asians) aged ≥40 years, 113 234 (5.0%) were diagnosed with non exudative and 17 181 (0.76%) with exudative AMD [2]. In a Chinese population aged ≥40 years, the prevalence of early, late, and neovascular AMD was 5.2%, 0.2% and 0.1%, respectively, and the incidence of per subject was 4.2%, 0.1%, and 0.1%, respectively [3]. The prevalence of AMD rises steeply with age. In a study with three racially similar populations of 14 752 individuals from North America, Europe, and Australia, AMD affects nearly 0.2% of the population aged 55 to 64 years, and 13% of the population older than 85 years [4].The estimated prevalence of late AMD was 0.08% at age 50, 0.33% at age 60, 1.38% at age 70, 5.60% at age 80, and 20.10% at age 90, respectively [5]. As global population ages, the burden on healthcare systems worldwide related to treating this chronic disease will be overwhelming.

AMD is a progressive degeneration of the macula, the portion of the retina used for central vision. Retina consists of the inner neural retina, and the outer retinal pigment epithelial (RPE) layer. The RPE layer sits on Bruch’s membrane, forms the outer blood–retina barrier, separates the neural retina from its choroidal blood supply, and maintains a physiological environment for photoreceptor function. This RPE monolayer is a main target in the development of AMD. The earliest stage of AMD is characterized by an accumulation of extracellular lipid– and protein–containing deposits, termed drusen, between the RPE and Bruch’s membrane. As AMD progresses, it can develop into two distinct forms of late or advanced AMD: “dry” AMD (geographic atrophy) and “wet” AMD (neovascular AMD). The “dry” AMD is the most common form (90%), characterized by the slow loss or blurring of central vision in spots due to significant RPE/ neuro retinal atrophy. The “wet” AMD is less common (10%), more severe, and may progress rapidly and cause the most severe vision loss because of proliferation and invasion of abnormal choroidal (or occasionally retinal) blood vessels and fluid leakage into the retina [6–9].

The exact causes and the underlying pathogenic mechanisms for AMD remain largely unknown, but numerous studies have established advanced age, smoking, and genetic predisposition as key risk factors. Other risk factors include low dietary intake of antioxidants, dietary fat intake, gender, race, ethnicity, cardiovascular disease, high blood pressure, cholesterol levels, estrogen levels, and light exposure [9,10]. The possible mechanisms for AMD include genetic, epigenetic and environmental factors related to RPE senescence, alterations in the complement pathway, increased inflammation, changes in the balance of growth factors, excessive lipofuscin accumulation, mitochondrial defects, and oxidative stress [6,8].Currently, there is neither a cure nor means of prevention for AMD [8,9]. Many completed and ongoing immune–based clinical trials for AMD have been ineffective [7]. There is, therefore, a critical need to identify new mechanisms for AMD, in order to develop unique preventive and therapeutic strategies for this age–related blinding disease.

The purinergic receptor P2X, ligand–gated ion channel, 7 (P2X7R; also known as P2RX7, P2X7 receptor, P2X7, P2X7 or P2Z) is an ATPgated cationic channel expressed by a variety of cell types including hematopoietic, epithelial, and neuronal cells [11,19]. The P2X7R is involved in oxidative stress, cell death and inflammatory processes, all of which have been linked to AMD.

This review will discuss the most recent advances in the P2X7R, focusing on the P2X7R in the RPE and its implications in AMD pathogenesis.

The P2X7 Receptor

Virtually all types of cells express plasma membrane receptors for extracellular nucleotides termed P2 receptors that are further categorized into P2X receptors and P2Y receptors [20]. So far, fifteen P2 receptors have been identified, including seven P2X receptor subunits (P2X1–7), and eight P2Y receptor subtypes (P2Y1,2,4,6,11,12,13,14). P2X receptors are ligand–gated, nonselective cation channels, ranging from 379 to 595 amino acids in length. Each subunit of P2X receptors is composed of two transmembrane domains (TM1 and TM2), a large extracellular loop, and intracellular N– and C–termini. P2X receptor subunits co–assemble to form functional homotrimeric or heterotrimic forms depending on tissue–specific expression and receptor subunits. P2X receptors are activated by extracellular ATP. Activation of P2X receptors causes influx of Ca2+ and Na2+ and efflux of K+.P2Y receptors are classical heterotrimeric G protein–coupled receptors featuring an extracellular N–terminus, seven transmembrane domains, and an intracellular C–terminus. P2Y receptors are activated by ATP, ADP, UTP and UDP.

Among seven P2X receptors, the P2X7R is unique in terms of both its structure and function. The human P2X7R gene is localized within a 55–kb region of chromosome 12q24, is highly polymorphic and has 13 exons that encode a 595 amino acid polypeptide [21]. The C–terminus (244 aa) of P2X7R is 120–200 amino acids longer than that of the other P2X receptors, and harbors multiple potential protein and lipid interaction motifs, which was thought to be pivotal in regulating its function [22]. Increasing evidence suggests that the C–terminusis critical for post–translational modification, cellular localization, oligomerization, protein–protein interactions and signaling pathway activation [23,24]. A schematic structure of the P2X7R is shown in (Figure 1).