P2 Receptors for Extracellular Nucleotides in the Central Nervous System: Role of P2X7 and P2Y2 Receptor Interactions in Neuroinflammation
- First Online:
- Cite this article as:
- Weisman, G.A., Camden, J.M., Peterson, T.S. et al. Mol Neurobiol (2012) 46: 96. doi:10.1007/s12035-012-8263-z
- 543 Views
Extracellular nucleotides induce cellular responses in the central nervous system (CNS) through the activation of ionotropic P2X and metabotropic P2Y nucleotide receptors. Activation of these receptors regulates a wide range of physiological and pathological processes. In this review, we present an overview of the current literature regarding P2X and P2Y receptors in the CNS with a focus on the contribution of P2X7 and P2Y2 receptor-mediated responses to neuroinflammatory and neuroprotective mechanisms.
KeywordsP2Y2 receptorP2X7 receptorNeuroprotectionNeuroinflammation
Extracellular nucleotides, such as adenosine 5′-triphosphate (ATP) and uridine 5′-triphosphate (UTP), are released from cells under a variety of physiological and pathological conditions whereupon they activate P2 nucleotide receptors on the surface of neighboring cells [1, 2]. P2 receptors are a diverse family of plasma membrane proteins that can be segregated into two subtypes: the P2X receptors that are ATP-selective cation channels and the P2Y receptors for ATP, UTP, or their metabolites that are coupled to heterotrimeric G proteins [3, 4]. To date, genes for seven P2X receptors and eight P2Y receptors have been cloned and their protein products have been extensively characterized in a variety of cell and tissue types [5, 6]. In the central nervous system (CNS), multiple P2X and P2Y receptor subtypes are expressed in neurons, glial cells, oligodendrocytes, macrophages, and endothelium where they regulate physiological responses, including neurotransmission, pain perception, phagocytosis, and maintenance of the blood–brain barrier [7–9]. Pathophysiological responses are also regulated by P2X and P2Y receptors, including the propagation of inflammation due to the release of nucleotide agonists from damaged or diseased cells [10–12]. This review describes the contributions of both P2X and P2Y receptors to cell specific functions in the CNS and focuses on the dual roles of the ionotropic P2X7 receptor (P2X7R) for ATP and the G protein-coupled P2Y2 receptor (P2Y2R) for ATP and UTP in the regulation of proinflammatory responses in the brain. Recent studies have found that the release of extracellular ATP from stressed or damaged cells of the CNS can activate microglial cell P2X7Rs, which increases cytokine release, e.g., interleukin-1β (IL-1β), and the phagocytic activity of microglial cells . Additionally, IL-1β has been shown to upregulate P2Y2R expression in neurons to promote neuroprotective responses . These findings are reviewed in this paper and suggest that both P2X7 and P2Y2 receptors are promising targets for the treatment of neurodegenerative and other inflammatory diseases.
P2X Receptors in the Central Nervous System
P2X receptors in the nervous system
Neurons, astrocytes, microglia
Cerebral cortex, superior cervical ganglia
Neurogenic smooth muscle contraction, platelet activation, neuron and glial responses
Cerebral cortex, cerebellum, hippocampus, striatum, habenula, substantia nigra, dorsal root ganglia, mesenteric ganglia
Nociceptive transmission, hyperalgesia, allodynia, pre- and postnatal neurogenesis
Dorsal root ganglia, spinal cord
Enhance glutamate and substance P release, neuropathic pain sensation
Neurons, astrocytes, microglia
Cerebellum, hippocampus, brainstem, spinal cord
Release of brain-derived neurotrophic factor, induce neuropathic pain, prostaglandin E2 release, synaptic strengthening, hypersensitivity to sensory stimuli
Cerebral cortex, cerebellum, hippocampus, hypothalamus, thalamus, olfactory bulb, globus pallidum, midbrain, and hindbrain
Interconnection of cortical areas, postsynaptic purinergic transmission
Cerebellum, hippocampus, purkinje neurons, pyramidal neurons, sensory ganglia
Rarely forms functional homomeric receptors
Neurons, astrocytes, microglia
Cerebral cortex, hippocampus, brainstem, nucleus accumbens, spinal cord
Release of proinflammatory cytokines, apoptosis, membrane pore formation, glutamate release, ATP release, induction of synaptic plasticity
Superior cervical ganglia
ATP-mediated physiological responses
ATP-evoked membrane currents
Dorsal root ganglia
Similar to P2X3, but with reduced desensitization
Dogiel type II neurons in myenteric plexus
ATP-mediated physiological responses
P2X1Rs have been shown to cause contraction of neurogenic smooth muscle [40, 41], platelet activation [42, 43], and neuronal [33, 44] and glial cell responses . Among the P2XRs, the P2X1R has the highest affinity for ATP (EC50 ~1 μM) . The P2X1R is often observed in a heteromeric complex with the P2X2R and P2X5R resulting in biophysical and pharmacological properties distinct from those observed when each of these receptor subtypes is expressed separately [47–52]. In superior cervical ganglia neurons, the P2X1R contributes to ATP-mediated responses by forming a heteromeric unit with the P2X2R , whereas ATP-evoked biphasic membrane currents in mouse cortical astrocytes are regulated by P2X1R/P2X5R heteromeric channels .
P2X2Rs are widely expressed in the CNS with predominant expression in the cerebral cortex, cerebellum, striatum, hippocampus, habenula, substantia nigra, dorsal ganglia neurons, mesenteric ganglia neurons, and glial cells [23, 24, 53–57]. The P2X2R is distinguished from other members of the P2XR family, since multiple splice variants exist in different mammalian species with diverse functional properties . Many studies have shown that P2X2Rs play a role in nociceptive transmission, hyperalgesia, and allodynia, particularly when present as functional heterotrimers with P2X3Rs [56, 59, 60]. The pharmacological properties of P2X2R/P2X3R are similar to the P2X3R, but the desensitization rate of the P2X3R is reduced by its interaction with the P2X2R . P2X2Rs and P2X2R/P2X3R have been implicated in pain processing ; however, with chronic pain, their functions are altered by the action of other P2XRs, especially those expressed in immune cells, such as microglia . In addition to interactions with P2X2Rs, P2X3Rs also form homotrimeric receptors that are prominently expressed in primary sensory neurons where they enhance the release of glutamate and substance P [32, 64–66], which contribute to both acute and chronic pain sensation . In vivo studies using P2X2R−/−, P2X3R−/−, and P2X2R−/−/P2X3R−/− mice have contributed significantly to our understanding of neuropathic and inflammatory pain sensation and have led to the development of therapeutic antagonists to these receptors [67, 68]. The P2X2R also has been suggested to play a role in pre- and postnatal neurogenesis .
The P2X4R is expressed throughout the central and peripheral nervous systems [29, 44, 70–72]. The P2X4R is upregulated in activated microglial cells after spinal cord or peripheral nerve injury where it appears to mediate the release of brain-derived neurotrophic factor and induce neuropathic pain . Recent studies provide evidence that the functional expression of P2X4Rs in tissue-resident macrophages regulates inflammation-dependent prostaglandin E2 release . Activation of homomeric P2X4Rs in hippocampal neurons has been suggested to contribute to synaptic strengthening and hypersensitivity to sensory stimuli [72, 75]. In addition, hippocampal synaptic transmission and long-term potentiation were abolished in P2X4R−/− mice . A unique characteristic of the P2X4R is its modulation by trace metals; copper inhibits whereas zinc and cobalt potentiate P2X4R activity . P2X4R activity has been shown to be modulated by the allosteric effector ivermectin . Heteromeric assembly of the P2X4R with the P2X1, P2X6, and P2X7 receptor subtypes has been described [77–79], although the functional relevance of these complexes in vivo is currently unknown.
The expression of the P2X5R subtype in the mouse CNS is most abundant in the olfactory bulb, cerebral cortex, globus pallidum, hippocampus, thalamus, hypothalamus, cerebellar cortex, and mid- and hindbrain nuclei . Although in vitro data have demonstrated ATP-evoked currents coupled to P2X5R activation, little is known about the physiological relevance of P2X5Rs in the CNS. Guo et al. speculate that P2X5R expression in the molecular layer of the cerebral cortex could play a role in interconnection of local cortical areas and P2X5R expression in the olfactory bulb suggests a role in fast excitatory postsynaptic purinergic transmission . In vitro studies have shown that activation of the homomeric P2X5R results in small, nondesensitizing currents, whereas activation of frequently observed heteromeric P2X5/P2X1 receptors results in slowly desensitizing ATP-evoked currents [48, 50]. A P2X5R−/− mouse has not yet been developed; however, it will be critical for evaluating the role of the P2X5R in vivo. Interestingly, a recent study indicates that most humans express only a nonfunctional isoform of the P2X5R .
In the CNS, the P2X6R is expressed in Purkinje cells in the cerebellum, pyramidal cells in the hippocampus, and sensory ganglia [22, 29, 83–85]. The ability of the P2X6R to form functional homomeric receptors is very low due to inefficient glycosylation of the N-terminus [86, 87]. P2X6Rs readily form functional heteromers with P2X2 and P2X4 receptors, where activation of one subtype potentiates the activity of the other . In the myenteric plexus, the P2X6R is expressed in Dogiel type II neurons where it likely regulates physiological responses to ATP as a heteromeric complex with P2X2Rs .
Among the P2X receptor subtypes, the P2X7 receptor has gained prominent recognition as a regulator of inflammatory responses . P2X7Rs are expressed in many types of cells, notably in immune cells where activation by ATP increases the release of proinflammatory cytokines and apoptotic cell death [91, 92]. The P2X7R was first cloned from rat brain  and, subsequently, has been found to be expressed in microglia, neurons, and astrocytes [39, 92, 94, 95]. The P2X7R requires high concentrations of ATP (>0.1 mM) for activation, although the photoaffinity ligand BzATP is a more potent agonist [96, 97]. Stimulation of the P2X7R regulates the gating of nonselective cation channels, mitochondrial and plasma membrane depolarization, the formation of plasma membrane pores, plasma membrane blebbing, and the production of reactive oxygen species (ROS), responses ultimately leading to cell death [10, 90, 97–103]. P2X7R activity is dramatically potentiated by decreasing the divalent cation concentration, indicating that ATP4− may be the active ligand [104–106]. P2X7Rs have been shown to mediate the release of neurotransmitters, e.g., glutamate, GABA, and ATP, and may be required for the induction of synaptic plasticity [38, 107, 108]. It also has been shown that P2X7R activation induces hypoxia- and caspase-dependent neuronal cell death [109, 110]. Activation of P2X7Rs in glial cells results in the release of the proinflammatory cytokines TNFα, IL-1β, and leukotrienes, thereby triggering or potentiating neuroinflammation [111–114], as described below. The P2X7R is upregulated in damaged nerves [115, 116] and in nerves obtained from neuropathic pain patients . In a mouse model of neuropathic pain, hypersensitivity to pain stimuli was completely absent upon deletion of the P2X7R . The P2X7R is also upregulated in microglia around β-amyloid plaques in a mouse model of Alzheimer’s disease (AD) where it mediates superoxide production . Enhanced expression of P2X7Rs also was observed in microglia derived from postmortem AD brains compared with glia obtained from nondemented brains . Furthermore, studies with a mouse model of Huntington’s disease suggest that P2X7Rs may play a role in disease pathogenesis . Therefore, the P2X7R receptor could represent a therapeutic target for treating neurodegenerative diseases.
P2Y Receptors in the Central Nervous System
P2Y receptors in the nervous system
Neurons, astrocytes, microglia, oligodendrocytes
Cerebral cortex, cerebellum, hippocampus, midbrain, caudate nucleus, putamen, globus pallidus, habenula, subthalamic nucleus, dorsal root ganglia, dorsal horn
Synaptic transmission modulation, provides neuroprotection by stimulating IL-6 release from astrocytes, brain development and repair, sensory reception
Neurons, astrocytes, microglia
Cerebral cortex, cerebellum, hippocampus, nucleus accumbens, spinal cord
Promote neurite outgrowth, stimulate α-secretase-dependent processing of amyloid precursor protein, increase phagocytosis of Aβ peptide, regulate intracellular calcium waves, stimulate proliferation, modulate pain sensation, increase cell motility
Neurons, astrocytes, microglia
Cerebral cortex, hippocampus
Synaptic transmission modulation, regulation of blood–brain barrier function, blood flow, metabolic trafficking, water homeostasis
Neurons, astrocytes, microglia
Cerebral cortex, cerebellum, hippocampus, amygdala, cingulate gyrus, putamen, nucleus accumbens, superior cervical ganglia, dorsal root ganglia
Stimulate phagocytic activity, neuroinflammatory responses
Cerebellum, hippocampus, parahippocampal gyrus, putamen, striatum, nucleus accumbens
Neurons, astrocytes, microglia, oligodendrocytes
Cerebral cortex, cerebellum, hippocampus, nucleus accumbens
Regulation of migration and chemotaxis
Modulation of synaptic transmission, modulates expression of cell survival genes
Cerebral cortex, cerebellum
Modulation of immune system’s anti-tumor response
The P2Y1R has a widespread distribution in mammalian brain, including the cerebral cortex, hippocampus, caudate nucleus, putamen, globus pallidus, habenula, subthalamic nucleus, midbrain, and cerebellum, as demonstrated in autoradiographic and immunohistochemical studies [144–146]. The P2Y1R is intensely expressed in Purkinje cells, in deep layers of the cerebral cortex, and in areas of the hippocampus sensitive to ischemia . P2Y1R immunoreactivity has also been observed in oligodendrocytes and astrocytes in brain white matter tracts and optic nerves [134, 147]. P2Y1Rs have been suggested to play important roles in glial cell functions . P2Y1R activation in astrocytes of hippocampal cultures has been suggested to provide neuroprotection from oxidative stress by increasing IL-6 release . P2Y1Rs are also expressed in microglial cells [116, 134, 144, 149, 150], rat neuroprogenitor cells , and various sensory neurons such as dorsal root ganglia and dorsal horn neurons [152–154]. Studies have suggested potential roles for P2Y1Rs in brain development and repair  and sensory reception [153, 155].
P2Y2R expression in rat primary cortical neurons is upregulated in response to IL-1β , a cytokine whose levels are elevated in the brains of AD patients [179, 180]. Subsequent activation of these upregulated P2Y2Rs in neurons promotes neurite outgrowth  and generates the non-amyloidogenic soluble APPα peptide, rather than neurotoxic Aβ1-42 peptide aggregates associated with AD . In mouse primary microglial cells, the P2Y2R is upregulated in the presence of Aβ1-42 and when activated can increase the phagocytosis and degradation of neurotoxic forms of Aβ [9, 182, 183]. In astrocytic cells, the P2Y2R has been suggested to contribute to synaptic transmission through the regulation of intracellular calcium waves  and upregulates anti-apoptotic protein expression to promote cell survival . Thus, P2Y2R upregulation in response to proinflammatory conditions likely serves a neuroprotective role in the CNS that requires contributions from both glial and neuronal P2Y2Rs, as described in more detail below.
The human P2Y4R is preferentially activated by uridine nucleotides, whereas the rat and mouse P2Y4Rs are stimulated equipotently by ATP and UTP [186–188]. P2Y4R mRNA is highly expressed in human brain . Single cell RT-PCR demonstrated the expression of P2Y4Rs in rat hippocampal pyramidal neurons . The expression of P2Y4Rs in astrocytes and microglial cells has been extensively documented [134, 137, 150, 186]. P2Y4Rs, as well as P2Y2Rs, are strongly expressed in glial endfeet in proximity to blood vessel walls  where their activation by ATP has been postulated to regulate blood–brain barrier function, blood flow, metabolic trafficking, and water homeostasis [190, 191].
The P2Y6R is activated by UDP and to a lesser extent UTP . In 18 areas of the human brain, the level of P2Y6R mRNA expression was highest in the amygdala, cingulate gyrus, nucleus accumbens, and putamen . Single cell RT-PCR revealed P2Y6R mRNA in 2 of 12 pyramidal neurons of rat hippocampus . In addition, P2Y6R mRNA has been demonstrated in superior cervical ganglion [44, 193] and dorsal root ganglion neurons [152, 153]. Functional studies have revealed the presence of P2Y6R activity in cerebellar and cortical astrocytes [134, 194]. P2Y6R activation has been shown to increase phagocytotic activity of microglia, postulated to occur in vivo in response to UTP released from damaged cells [195, 196]. Consistent with this hypothesis, injury has been shown to induce increased P2Y6R expression in astroglial cells . In microglial cells stimulated overnight with bacterial lipopolysaccharide, P2Y6R-mediated increases in the intracellular calcium concentration were observed, suggesting a role for the P2Y6R in neuroinflammation .
The P2Y11R can couple to multiple G proteins to regulate the activity of two second messenger systems: adenylate cyclase-mediated cAMP production and PLC-dependent production of IP3 and DAG that modulate calcium release from intracellular storage sites and protein kinase C activation, respectively . The P2Y11R is activated by ATP or ADP, but not by uridine nucleotides . P2Y11R mRNA expression is prominent in nucleus accumbens, parahippocampal gyrus, putamen, and striatum . The P2Y11R has been localized to single rat hippocampal pyramidal neurons and to Purkinje cells in adult rat cerebellum [34, 198]. Inhibition of the P2Y11R has been shown to delay ATP-induced neutrophil apoptosis, suggesting a role for the P2Y11R in the regulation of neuroinflammatory responses .
The P2Y12R is widely distributed in the brain with a pattern consistent with expression in astrocytes [200, 201]. RT-PCR has demonstrated the presence of P2Y12R mRNA in single rat hippocampal pyramidal neurons . Cortical and cerebellar astrocytes and astrocytes in the rat nucleus accumbens also express P2Y12Rs [134, 165, 202]. P2Y12Rs have been suggested to regulate the migration of microglial cells towards damaged neurons . P2Y12R expression in microglia is robust in the “resting” state, but dramatically reduced in activated microglia, and P2Y12R−/− mice have significantly diminished directional branch extension toward sites of cortical damage in vivo . In contrast, a recent study concludes that the expression of the P2Y12R in the CNS is restricted to oligodendrocytes . It also has been suggested P2Y12Rs contribute to the migration and adhesion of glial cell processes to axons during pre-myelination .
The P2Y13R is activated by ADP  and 2-methylthio ADP is a potent synthetic agonist , similar to the P2Y12R; however, ATP and ATP analogues are inactive at the P2Y13R . P2Y13R expression has been localized to brainstem astrocytes and glutamatergic neurons [145, 189, 209]. P2Y13Rs, along with P2Y1 and P2Y12 receptors, have been shown to regulate Na+ and Cl−-dependent synaptic glycinergic neurotransmitter transporters to increase transport of glycine from the synaptic cleft, thereby maintaining quantal glycine levels in inhibitory synaptic vesicles [209, 210]. The P2Y13R can also activate the glycogen synthase kinase-3 (GSK-3)-dependent phosphatidylinositoI 3-kinase (PI3K)/Akt survival pathway to increase translocation of the GSK-3 substrate β-catenin to the nucleus, where it modulates expression of cell survival genes .
The P2Y14R is expressed in astrocytes , and RT-PCR and single cell Ca2+ imaging has documented the functional expression of P2Y14Rs in rat cortical and cerebellar astrocytes [134, 202]. Agonists of the P2Y14R include UDP-glucose, UDP-galactose, UDP-glucuronic acid, and UDP-N-acetylglucosamine, but not adenine or uridine nucleotides [212–214]. UDP-glucose has been shown to be released from a variety of cell lines, and UDP-glucose levels can exceed those of ATP under various conditions . Functionally, P2Y14Rs in primary microglial cells from rat brain have been shown to modulate the calcium response to bacterial lipopolysaccharide . P2Y14Rs expressed in immature dendritic cells have been suggested to play a role in the immune system’s anti-tumor response [143, 216].
Neuroinflammatory P2X7Rs Regulate Neuroprotective P2Y2R Expression
P2X7R activation contributes to neuroinflammation by promoting mitochondrial and plasma membrane depolarization, the formation of plasma membrane pores, plasma membrane blebbing, and the production of ROS [10, 90, 98–103]. In addition, P2X7R activation promotes neuroinflammation by causing the release of proinflammatory cytokines, such as IL-1β and TNF-α [90, 217, 218], and activation of MAP kinases and NF-κB, resulting in upregulation of proinflammatory gene products, including COX-2, chemokines, and cell adhesion molecules [90, 219–223] and the P2Y2R . Importantly, P2X7R-mediated pore formation initially increases ATP release through P2X7R interactions with a pannexin hemi-channel in cells . P2X7R-mediated IL-1β and ATP release is a mechanism whereby the P2X7R regulates functional P2Y2R expression in neurons and provides agonist for the activation of the upregulated P2Y2R and other P2 receptors . ATP release also can occur from activated microglia and astrocytes in response to oxidative stress , following neuronal excitation [224, 225], via volume-activated anion channels , or upon exposure of cells to fibrillar or oligomeric forms of amyloidogenic Aβ1-42 peptides [157, 183, 226, 227]. Thus, P2X7 and P2Y2 receptors may represent promising targets to control inflammatory responses associated with neurodegenerative diseases. Indeed, mice deficient in the P2X7R (P2X7R−/− mice) exhibit decreased inflammatory responses [117, 228–230], including a reduction in pulmonary fibrosis in a mouse model of lung inflammation  and the absence of pain hypersensitivity in mouse models of chronic inflammation and neuropathic pain . Phase I and II clinical trials for selective P2X7R antagonists are presently underway for the treatment of rheumatoid arthritis and other inflammatory diseases [231, 232].
Upregulation of the P2Y2R in response to P2X7R activation appears to promote neuroprotective responses. The ability of the P2Y2R to stimulate neuroprotective responses depends upon the coupling of the receptor to intracellular signaling pathways that are distinct among the P2YR family (see Fig. 2). These responses associated with P2Y2R upregulation include the outgrowth and stabilization of dendritic spines [9, 176, 233], which requires RGD-dependent P2Y2R/αv integrin interaction to stimulate Rac and Rho and induce cytoskeletal rearrangements [173, 174] and upregulation of neurofilament M and neurofilaments that promote neurite outgrowth . P2Y2Rs also require Src to co-localize with the tyrosine receptor kinase A in the presence of nerve growth factor, a pathway that regulates neurite outgrowth and cell division via the activation of p38 and ERK1/2 MAP kinases [234, 235]. In neural progenitor cells isolated from the subventricular zone of adult mouse brain, P2Y2R activation was shown to induce proliferative responses such as the transient activation of the EGFR, the MAP kinases ERK1/2, and the transcription factor CREB . Other studies indicate that the P2Y2R mediates the activation of PI3-kinase/Akt and MAP kinases to inhibit apoptosis of PC12 pheochromocytoma cells and dorsal root ganglion neurons [235, 237]. P2Y2R upregulation by IL-1β and subsequent activation in primary cortical neurons increases amyloid precursor protein (APP) processing via activation of matrix metalloproteases (i.e., α-secretases), a neuroprotective response that produces a non-amyloidogenic soluble APP peptide (i.e., sAPPα) rather than neurotoxic amyloidogenic Aβ peptide . IL-1β is known to stimulate neuronal synthesis of APP and increase the release of neurotoxic Aβ, which further enhances IL-1β production . We postulate that upregulation of the P2Y2R induced by IL-1β in vivo counteracts the potential neurotoxic effects of IL-1β-dependent elevations in APP levels by promoting generation of non-toxic sAPPα instead of Aβ. Thus, P2Y2R upregulation in the CNS may delay the progression of neurodegeneration associated with reactive gliosis and chronic inflammation in AD and other neurological disorders.
Glial cells, including astrocytes and microglia, play important neuroprotective roles. Astrocytes contribute to the maintenance of the blood–brain barrier (BBB) [239–241], which prevents invasion of pathogenic, neurotoxic substances into the brain from the circulation [242, 243]. Astrocytes also release neurotrophic factors that regulate neuronal survival and sprouting and supply energy substrates to neurons . Astrocytes have been shown to release ATP under a variety of pathological conditions [245–247] and ATP levels are elevated sufficiently by inflammation in vivo to activate P2 nucleotide receptors . P2Y2Rs are upregulated in reactive astrocytes of the rat cortex and nucleus accumbens in response to mechanical injury  and have been suggested to enhance astrocyte survival [185, 248]. In addition, interactions between the P2Y2R and integrins have been demonstrated to regulate the migration of astrocytes [173, 174, 249]. It also has been shown that P2X7R activation increases the expression of P2Y2Rs in rat astrocytes  likely via P2X7R-mediated IL-1β release [112, 226, 242, 251–253].
Microglia have important immunoregulatory functions in the CNS. Injury or other insults to the CNS trigger transformation of quiescent microglia into activated phenotypes, i.e., phagocytic macrophages [254, 255]. Activated microglia have neuroprotective functions [255–259], although sustained activation can be neurotoxic [256, 260–262]. Microglial cell activation by proinflammatory cytokines has been shown to increase cell motility and proliferation , responses associated with reactive gliosis in neurodegenerative diseases. Adenine and uridine nucleotides have been shown to increase the motility of microglial cells [195, 204, 264] via activation of P2Y2 and P2Y12 receptors [204, 265] and ATP release can significantly increase microglial process extension towards a site of injury . The endogenous expression of P2Y2Rs has been reported in mouse microglia [267, 268] where they have been shown to regulate responses associated with reactive gliosis [7, 9, 165, 185, 248, 249]. For example, the P2Y2R agonists UTP and ATP released from apoptotic cells have been shown to induce migration of phagocytic cells , which presumably serves to enhance the clearance of cellular debris. Microglial cells exposed to Aβ also have been shown to release ATP [226, 270]. Studies using peritoneal macrophages in mice have shown that stimulation of P2Y2 and P2Y12 receptors induces the formation of lamellipodia in membrane protrusions which is required for cell motility . Co-activation of P2Y2 and P2Y6 receptors in human monocytes enhances migration, a response shown to involve toll-like receptor-induced IL-8 release [272, 273]. We have found that P2Y2R activation increases mouse microglial cell migration and phagocytic activity, such as the uptake of neurotoxic oligomeric Aβ1-42, responses that are absent in microglia from P2Y2R−/− mice . Both activated astrocytes and microglia internalize and degrade Aβ [274–278], a pathway that reduces Aβ toxicity in neurons that is postulated to play a role in the progression of AD. We speculate that P2Y2Rs in glial cells contribute to the phagocytosis and degradation of neurotoxic forms of Aβ in vivo under conditions where elevated levels of ATP release and IL-1β generation occur [279, 280].
This review summarizes data indicating that seven ionotropic P2X and eight G protein-coupled P2Y receptors for extracellular nucleotides are expressed in cell types comprising the CNS and these P2X and P2Y receptor subtypes have been shown to regulate diverse physiological and pathological responses under a variety of conditions. Recent studies indicate that activation of the P2X7R subtype during inflammation causes upregulation and activation of P2Y2Rs to promote neuroprotective responses. These findings suggest that ATP released from injured or stressed cells in the CNS can activate P2X7Rs in microglial cells to increase the release of proinflammatory cytokines, such as IL-1β, that increase the expression of the P2Y2R, particularly in neurons. Other studies indicate that both P2X7R and P2Y2R activation can increase phagocytosis of neurotoxic forms of Aβ and that activation of the P2Y2R increases non-amyloidogenic APP processing, neuroprotective responses that are postulated to delay the onset or retard the progression of neurodegenerative diseases, such as Alzheimer’s disease. In addition, P2Y2R activation in neurons has been shown to increase neurite outgrowth. The P2Y2R contains multiple motifs that enable its activation to directly couple to integrin and growth factor receptor signaling pathways that play a role in cell proliferation and differentiation and cytoskeletal rearrangements that are critical for tissue repair. Thus, the studies described in this review suggest that the P2X7R and P2Y2R are promising targets for the treatment of neurodegenerative diseases.