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Central Nervous System Agents in Medicinal Chemistry, 2007, 7, 223-229

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Involvement of Uridine-Nucleotide-Stimulated P2Y Receptors in Neuronal Growth and Function Mehmet Canseva,b,* a

Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Pharmacology and Clinical Pharmacology, Uludag University School of Medicine, Gorukle, Bursa 16059, Turkey b

Abstract: The uridine nucleotides UTP, UDP and UDP-sugars produce a variety of effects by activating specific G protein-coupled P2Y receptors, i.e., the P2Y2, P2Y4, P2Y6 and P2Y14 variants. Except for P2Y14 which has recently been defined, stimulation of P2Y receptors by UTP and/or UDP augments proliferation of adult multipotent neural stem cells; stimulates dopaminergic differentiation in human mesencephalic neural stem cells; and enhances neurite outgrowth in nerve growth factor-differentiated PC12 cells and cultured DRG neurons. UTP and/or UDP have been shown to affect neuronal function by depolarizing neurons from cultured amphibian sympathetic ganglia; increasing firing rates of neurons; enhancing presynaptic glutamate release and promoting long-term potentiation; and by stimulating noradrenaline release from cultured sympathetic neurons. Furthermore, by activating P2Y receptors, UTP and/or UDP exhibit neuroprotective effects via induction of microglial convergence and reactive astrogliosis; protection from serum starvation-induced apoptosis; and stimulation of -secretase-dependent APP processing and sAPP release. Antagonism of uridine- nucleotide-stimulated P2Y receptors or the second messengers they generate, or degradation of extracellular uridine nucleotides, can block the effects mediated by these receptors. These observations suggest that uridine-nucleotide-stimulated P2Y receptors may constitute possible therapeutic targets for diseases affecting neuronal survival or function.

Keywords: P2Y receptors, uridine, UDP, UTP, neurite outgrowth, neuronal function, survival. INTRODUCTION Extracellular nucleotides are ligands for a variety of ionotropic P2X and metabotropic P2Y receptors. While P2X receptors recognize adenine nucleotides, P2Y receptors are affected by both adenine and uridine nucleotides. Members of the P2Y family are G protein-coupled receptors, and are widely distributed throughout the body, including the brain [1]. To date, eight P2Y receptors of human origin (P2Y1, 2, 4, 6, 11, 12, 13, 14) have been cloned and characterized [2]. [The missing numbers represent either nonhuman orthologs or receptors having some sequence homology to P2Y receptors but for which there is no functional evidence of responsiveness to nucleotides]. P2Y receptors that recognize adenine, but not uridine, nucleotides comprise the P2Y1, P2Y 11, P2Y12, and P2Y13 subtypes. P2Y1 receptors are located mainly in epithelial and endothelial cells, platelets, immune cells, and osteoclasts, while main localization of P2Y11 receptors include spleen, intestine, and granulocytes; they both function via Gq/G11 and PLC- activation [1]. P2Y12 receptors, which are located mainly in platelets and glial cells, function via activation of Gi/o proteins and inhibition of adenylate cyclase [1]. P2Y13 subtypes also activate Gi/o proteins, and are located mainly in spleen, brain, lymph nodes and bone marrow [1]. UTP, UDP, and UDP-sugars can activate one or more of the P2Y2, P2Y4, P2Y6, and P2Y14 receptor types. UTP acti*Address correspondence to this author at the 43 Vassar Street, 46-5027 MIT, Cambridge MA, 02139, USA; Tel: +1 617 253 8371; Fax: +1 617 253 6882; E-mail: [email protected] 1871-5249/07 $50.00+.00

vates P2Y2 (which is equipotently activated by ATP) [3] and P2Y 4 [4] receptors, while the physiological agonist for P2Y6 receptors is UDP [5] (Table 1). P2Y2, P2Y4, and P2Y6 receptor stimulation, through coupling to phospholipase C (PLC), increases intracellular concentrations of diacylglycerol (DAG), inositol trisphosphate (IP3) and intracellular calcium [6,7]. P2Y14 receptors are stimulated by UDP-sugars, principally by UDP-glucose [8] (Table 1). This inhibits adenylate cyclase activity, via coupling to Gi proteins [8]. There is no known antagonist for P2Y14 receptors and their functions are not yet characterized. Hence, this article will not cover further discussion about P2Y14 receptors. That uridine nucleotides affect neuritogenesis and neuronal function via stimulation of P2Y receptors has been repeatedly demonstrated, mainly using in vitro assay systems [9-11]. Increased neurite outgrowth following stimulation of P2Y receptors by uridine nucleotides, which is accompanied by increased expression of certain neurofilament proteins, can be blocked by P2Y receptor antagonists or by apyrase, a drug that degrades extracellular nucleotides [11,12]. Evidence also is available that uridine nucleotides stimulate neuronal proliferation and differentiation during development [13]. Moreover, uridine-nucleotide-stimulated P2Y receptors can mediate such signaling events as release of the neurotransmitters noradrenaline and glutamate [14-16] and longterm potentiation [17], and can protect neurons by, for example, stimulating astrogliosis [18]; antagonizing apoptosis [19]; or preventing -amyloid deposits [20]. Such P2Yreceptor-mediated actions of uridine nucleotides could perhaps underlie possible treatments for ischemic or for neurodegenerative diseases such as Alzheimer’s. This article © 2007 Bentham Science Publishers Ltd.

224 Central Nervous System Agents in Medicinal Chemistry, 2007, Vol. 7, No. 4

Table 1.

Mehmet Cansev

Agonist and Antagonist Profiles of Uridine-Nucleotide-Stimulated P2Y Receptors

Receptor

Agonist

Antagonist

P2Y2

UTP = ATP

Suramin, Reactive Blue 2

P2Y4

UTP > ATP

PPADS, ATP (in humans), Reactive Blue 2,

P2Y6

UDP > UTP

Reactive Blue 2, PPADS, Suramin

P2Y14

UDP-sugars

N/A

reviews the mediation by P2Y receptors of the effects of uridine nucleotides on neuronal growth, differentiation and function, as well as on neurotransmission and neuroprotection. It also summarizes possible therapeutic uses for uridine-nucleotide-stimulated P2Y receptor agonists in diseases affecting neuronal survival or function. NEURONAL PROLIFERATION, DIFFERENTIATION AND GROWTH Both cultured neurons [21] and glial cells [22-24] functionally express P2Y2, P2Y4, and P2Y6 receptors which are also detected in human brain [25]. A growing body of evidence now suggests that P2Y receptors mediate effects of uridine nucleotides on neuronal proliferation, differentiation and neurite outgrowth. In the presence of growth factors (e.g., nerve growth factor, fibroblast growth factor) UTP as well as the adenine nucleotides ATP and ADP, augmented proliferation of adult multipotent neural stem cells derived from adult rodent subventricular zone, a brain region in which neurogenesis is believed to persist [26]. This effect involved activation of P2Y1 and P2Y2 receptors by their agonists, including UTP, and was abolished by prior application of the nonspecific P2 receptor antagonists suramin and PPADS [27]. Moreover, in the presence of various growth factors, UTP enhanced the proliferation of neurospheres cultured from the adult mouse subventricular zone [26] and human mesencephalic neural stem/precursor cells [13]. UTP also stimulated dopaminergic differentiation in the latter cell line, increasing the number of tyrosine hydroxylase-positive cells by 267% and the levels of tyrosine hydroxylase enzyme protein by 319% [13]. Similarly, UDP enhanced tyrosine hydroxylase protein levels by 194%, suggesting the involvement of P2Y6 receptors as well as of P2Y2 and P2Y4. Suramin or PPADS also blocked dopaminergic differentiation in these cells, confirming the involvement of P2Y receptors in this process. These observations suggest a role for the uridine-nucleotide-stimulated P2Y receptors that are expressed in developing brains [28-31] in the modulation of neuronal development. Neuronal differentiation is a complex process involving changes in the electrophysiological and morphological features of neurons, characterized by dendritic and axonal outgrowths, termed neurite outgrowth, that facilitate synaptic connections. The involvement of P2Y receptors in neurite outgrowth has been repeatedly demonstrated in PC12 cells [9,11], human SH-SY5Y neuroblastoma cells [10], cultured

dorsal root ganglion (DRG) neurons [9,32] and mouse sciatic nerve, in vivo [9]. Nerve growth factor (NGF)-differentiated PC12 cells, when treated with uridine or UTP for 4 days, exhibited an increased number of neurites (by about 20%) per cell [11]. This effect was accompanied by similar elevations in levels of the two neurofilament proteins, Neurofilament-M and Neurofilament-70, known to be enriched in neurites [33]. Furthermore, either uridine or UTP treatment increased IP3 turnover in PC12 cells [11], suggesting one mechanism by which neurite outgrowth had been enhanced, inasmuch as increased intracellular Ca+2 has been shown to be associated with this process [34]. Lower concentrations of UTP (10 μM) than of free uridine (50 μM) increased neurite outgrowth, and the effects of both compounds were abolished by the nucleotide-degrading compound apyrase [11]. This was interpreted as indicating that, in activating P2Y receptors to enhance neurite outgrowth, uridine works via UTP. Confirming this hypothesis, P2Y receptor antagonists blocked the effects of uridine and UTP on neurite outgrowth [11], as had previously been reported [12]. These observations suggest the involvement of P2Y receptors stimulated by uridine nucleotides, in neuronal differentiation, growth, and perhaps, survival. The mechanisms by which uridine nucleotide-stimulated P2Y receptors enhance neurite outgrowth are not fully characterized. However, that various intracellular molecules known to mediate neuronal differentiation and growth are activated by P2Y receptor stimulation has been well established [9,10,32]. Uridine nucleotide-stimulated P2Y receptors may enhance neurite outgrowth by potentiating the activation of neurotrophic-factor-associated intracellular molecules. Indeed, P2Y2 receptor activation has been shown to enhance neurite outgrowth in NGF-treated PC12 cells and cultured DRG neurons [32] by a mechanism involving the activation of extracellular signal-related kinase 1/2 (ERK1/2), a factor which has been implicated in neuronal differentiation and growth [9,32]. The cross-talk between P2Y2 receptors and NGF receptors (receptor tyrosine kinase A; TrkA) was found to be mediated by Src family kinases (SFK). Similarly, in human SH-SY5Y neuroblastoma cells, UTPstimulation of P2Y4 receptors led to the activation of cyclindependent kinase 5 (Cdk5) [10], another intracellular signaling molecule associated with a neurotrophic factor [35]. (This factor is involved in cross-talk with the extracellular signal-related kinases (ERKs) and is considered the major kinase phosphorylating the neurofilaments in vivo [36]). On

Involvement of Uridine-Nucleotide-Stimulated P2Y Receptors

Central Nervous System Agents in Medicinal Chemistry, 2007, Vol. 7, No. 4 225

the other hand, enhancement of neuronal growth by P2Y receptor stimulation may also involve induction of intracellular mechanisms that are not associated with neurotrophic factors. For example, stimulation of P2Y2 receptors, by a mechanism dependent on elevation of intracellular Ca+2, caused the activation of mitogen-activated protein (MAP) kinase by activating protein kinase C (PKC) [37]. [Fig. (1) overviews intracellular mechanisms proposed to be involved in neurite outgrowth and survival by utilizing uridinenucleotide-stimulated P2Y receptors]. Enhanced activation of intracellular mechanisms by uridine nucleotide-stimulated P2Y receptors, regardless of dependence on growth factors, may lead to enhanced expression of genes implicated in neurite outgrowth. However, enhanced gene expression probably is not the only mechanism whereby neurons grow and differentiate, inasmuch as these processes require that the quantities of membranes, and thus of their major content, the phosphatides also be increased per cell. It is not yet known whether stimulation by UDP or UTP of P2Y receptors activates mechanisms involved in membrane phosphatide synthesis. SIGNALING, NEUROTRANSMISSION, LONG-TERM POTENTIATION The existence of cell surface receptors for uridine nucleotides suggests that these compounds are released into the extracellular environment and produce intracellular effects by stimulating such surface receptors. No direct evidence has been presented that uridine nucleotides are released from neuronal synapses, however both basal and mechanicallystimulated release from glial cells, caused by changing the medium [38] or by oxygen-glucose deprivation [39] have been described [38-42]. Furthermore, ectonucleotidases [41,43] and ecto-nucleoside diphosphokinases [44] may

regulate extracellular concentrations of uridine nucleotides by degrading or generating these compounds. These observations strongly suggest that uridine nucleotides function as extracellular signaling molecules [45,46]. Indeed, exogenous administration of UTP and UDP has been shown to depolarize neurons from cultured amphibian sympathetic ganglia [47]. Since a P2Y receptor nomenclature had not been established at that time, this study was unable to identify the receptor type involved in the effect. More recently, UTP administration has been found to increase the firing rates of neurons in posterior hippocampal slices, and to enhance network activity (by 45%) assessed using multielectrode array recordings of primary posterior hippocampal cultures by stimulating P2Y4 receptors [31]. Furthermore, uridine nucleotides may interact with fast excitatory systems to affect synaptic transmission. Indeed, UTP and UDP have been shown to enhance presynaptic glutamate release and to promote long-term potentiation (LTP) mediated by glutamatergic synaptic transmission [17]. Their effects were independent of NMDA receptors or postsynaptic calcium influx, and were blocked by reactive blue-2, which led authors to conclude the involvement of presynaptic P2Y4 receptors [17]. [It should be noted that no other antagonist was tested, and reactive blue 2 is not a specific inhibitor for P2Y4 receptors]. The involvement of uridine nucleotides in neurotransmission apparently is not limited to presynaptic release of glutamate [17], and may include such other transmitters as noradrenaline. By activating P2Y receptors [14,48], and, perhaps also by inhibiting M-type K+ channels [16,49], UTP or UDP was shown to stimulate noradrenaline release from rat [14-16] and mouse [48] cultured sympathetic neurons. On the other hand, UTP did not cause noradrenaline release in undifferentiated or NGF-differentiated PC12 cells [50]. The authors did not find upregulation of P2Y receptors following

Fig. (1). Proposed intracellular mechanisms involved in neurite outgrowth and survival by utilizing uridine-nucleotide-stimulated P2Y receptors.


NGF stimulation (although no data regarding P2Y2 receptor protein expression following 72 hours of NGF differentiation were presented) and suggested that intracellular Ca+2 concentrations following UTP administration might not have increased to an extent sufficient enough to stimulate the release of noradrenaline [50]. The difference in cell types examined may explain the discrepancy in results obtained from PC12 cells and from cultured sympathetic neurons, inasmuch as uridine nucleotides, but not adenine nucleotides, do enhance noradrenaline release in mouse cultured sympathetic neurons [48]. Besides, the differentiation of PC12 cells by exposure to NGF for 3 days has been shown to increase the expressions of uridine-nucleotide-recognizing P2Y receptor proteins, including P2Y2 [11]. These observations suggest the view that uridine-nucleotide-activated P2Y receptors are involved in such neuronal functions as neurotransmission and LTP production. NEUROPROTECTION AND SURVIVAL Pathologic conditions such as traumatic brain injury, ischemia or neurodegeneration can cause death of brain cells. Such cellular death can cause the release into the brain’s extracellular fluid (ECF) of compounds which affect survival of nearby neurons. Some of the released compounds may cause damage to other neurons, while some reportedly are neuroprotective. Uridine nucleotides released from damaged brain cells may modulate processes that follow pathologic insults, probably by acting on P2Y receptors. Evidence exists for the involvement of these receptors in enhancement of neuronal survival through various mechanisms. For example, parenchymal microglia, the principal immune cells of the brain respond to traumatic brain injury by rapidly projecting microglial processes to the site of injury, thus establishing a potential barrier between the healthy and injured tissue; they also phagocytose dead cells and clear the cellular debris [51]. Microglia are known to express functional P2Y receptors [52] and to respond to purines and pyrimidines [53]. Indeed, UTP-induced rapid microglial convergence has been demonstrated in an in vivo study which characterized microglial responses to focal brain injury [54]. Although the type of receptor mediating microglial response was not determined, this effect may have involved activation of a UTP-recognizing P2Y receptor, inasmuch as P2Y receptor antagonists such as reactive blue-2 and PPADS markedly reduced the number of microglial processes converging towards the injury area after laser ablation, as well as their motility [54]. In response to brain injury, uridine nucleotides may also induce reactive astrogliosis characterized by increased expression of glial fibrillary acidic protein (GFAP), and by cell migration and proliferation [55] to form a barrier between damaged and healthy tissue [56]. Indeed, UTP stimulation caused reactive astrogliosis, as assessed by GFAP expression, in primary cultures of rat cortical astrocytes subjected to serum-free medium [18]. UTP-induced astrocyte migration required the interaction of P2Y2 receptors with v3/5 integrins inasmuch as silencing P2Y2 receptors by small interfering RNA (siRNA) and anti-v integrin antibodies prevented the effect [18]. The phosphatidylinositol-3 kinase (PI3-K)/protein kinase B (Akt) and the mitogen-activated

Mehmet Cansev

protein kinase/extracellular signal-regulated kinase (MEK/ ERK) pathways were also found to be activated [18]. The involvement of P2Y2 receptors in astrocytic responses to injury was confirmed in another study which showed P2Y 2 receptor up-regulation following subjection of cultured astrocytes to oxygen-glucose deprivation, or following UTP administration [39]. These observations suggest the involvement of UTP-stimulated P2Y receptors, in particular P2Y2, in glial response to further protect neurons from brain injury. Another mechanism for increasing neuronal survival may include inhibition of apoptosis. Stimulation of P2Y2 receptors, as demonstrated by siRNA and genetic knock-out models, caused protection from serum starvation-induced apoptosis in PC12 cells and in cultured DRG neurons [19]; the effect involved activation of intracellular signaling molecules including ERK and Akt [19]. Furthermore, stimulation by UTP of recombinant P2Y2 receptors expressed in a human 1321N1 astrocytoma cell line that lacked endogenous P2 receptor expression caused up-regulation of the antiapoptotic bcl-2 and bcl-xl genes; down-regulation of the proapoptotic bax gene; and a reduction in bax/bcl-2 mRNA expression ratio [57]. Expression of the genes for neurotrophins, neuropeptides and growth factors (e.g., nerve growth factor 2; neurotrophin 3; glia-derived neurite-promoting factor) as well as for astrocyte GFAP and for proteins indicated in survival (e.g., extracellular matrix proteins CD44 and fibronectin) also were up-regulated following P2Y2 receptor stimulation. As would be anticipated from an earlier demonstration of neurite outgrowth [11], this study also showed that conditioned medium from human 1321N1 astrocytoma cells expressing P2Y2 receptors treated with 100 μM UTP for 24 hours contained a factor that stimulated neurite outgrowth in PC12 cells to an extent comparable to treatment of the cells with NGF for the same period of time [57]. On the other hand, neurite outgrowth in PC12 cells did not occur with conditioned media from untreated 1321N1-P2Y2 cells, nor from untransfected (P2Y2 receptor null) 1321N1 cells treated with UTP. These observations suggest the involvement of uridine nucleotide-stimulated P2Y receptors, particularly the P2Y2 type, in preventing apoptotic cell death in neurons and glial cells, and further confirm a role for these receptors in enhancing neurite outgrowth under such pathologic conditions. Yet another neuronal survival mechanism induced by uridine nucleotides may involve protection from neurodegeneration by preventing deposition of -amyloid, the main component of the senile plaques seen in Alzheimer’s disease brains. These depositions are produced after the amyloid precursor protein (APP) is processed by - and -secretases, while alternative cleavage of APP within the amyloid- domain by -secretase releases the non-amyloidogenic product sAPP [58]. Enhanced production and release of sAPP fragments may confer benefit in neuroprotection, inasmuch as sAPP fragment has both neurotrophic [59] and neuroprotective [60,61] properties. Recently, uridine-nucleotidestimulated P2Y receptors have been shown to stimulate such process; stimulation of recombinant P2Y2 receptors expressed in human 1321N1 astrocytoma cell line by UTP enhanced -secretase-dependent APP processing and sAPP release in a time- and dose-dependent manner [20]. The ef-

Involvement of Uridine-Nucleotide-Stimulated P2Y Receptors


fect was independent of intracellular Ca+2 release or protein kinase C activation, but involved the activation of ADAM10 and ADAM17/TACE, molecules associated with both constitutive and receptor-regulated sAPP release. The enhanced production, and release by UTP activation of P2Y2 receptors of the neurotrophic and neuroprotective fragment sAPP [20] can, probably, reduce formation of the amyloidogenic and neurodegenerative fragment A [62] strongly suggests that uridine-nucleotide-stimulated P2Y receptors can promote neuronal viability in diseases associated with excess -amyloid in brain (e.g., Alzheimer’s disease). POSSIBLE THERAPEUTIC NUCLEOTIDES

USES

OF

URIDINE

Uridine is a precursor for phosphatide synthesis via the Kennedy pathway [63] Fig. (2). Orally-administered uridine increases uridine concentrations in plasmas of experimental animals or humans [64-66]. Uridine then is rapidly taken up into brain’s ECF mainly via the concentrative transporter CNT2 [67] and the equilibrative nucleoside transporters, ENT1 [68] and ENT2 [69] located at the blood-brain barrier (BBB) (reviewed in [66]). Once in brain’s ECF, uridine enters the brain cells mediated by members of the equilibrative and concentrative nucleoside transporter families [68,70], and is then phosphorylated by uridine cytidine kinase (UCK) [71] to produce such uridine nucleotides as UDP and UTP [65]. UTP is converted to cytidine triphosphate (CTP) [72], the usual rate-limiting compound in the Kennedy cycle of phosphatidylcholine (PC) synthesis Fig. (2). Hence, exogenous uridine increases the synthesis [65] and levels [73] of membrane phosphatides and enhances the quantities of brain membranes, particularly synaptic membranes [73].

tracellular UTP or UDP in vivo, and their involvement in the above-mentioned effects under normal conditions are not known, this mechanism could underlie, at least in part, some of the effects generated by exogenously administered uridine sources in vivo. (Reported effects of uridine on sleep [74] and seizures [75], and of a uridine pro-drug in Huntington’s disease [76] will not be discussed since no P2Y receptormediated mechanism was proposed in these studies). The consequences of stimulating P2Y receptors by uridine nucleotides suggest therapeutic uses for these compounds. Increased responses of cultured glia to oxygenglucose deprivation [18,39]; blockade of apoptotic mechanisms in serum-starved cells [19,57]; and enhanced convergence of microglia following focal brain injury caused by direct intracranial administration of UTP [54] all suggest a role for uridine nucleotides in treating ischemia or other brain injury. Also, increased neurite branching and outgrowth [9,11], and enhanced release of non-amyloidogenic and neuroprotective sAPP [20] suggest the possibility that uridine nucleotides might have a use in neurodegenerative diseases such as Alzheimer’s. Furthermore, since uridine nucleotide activation of P2Y receptors stimulates neurite outgrowth [11] and induces synaptic glutamatergic transmission and LTP [17] the nucleotides could promote learning and memory since these processes are associated with LTP [77]. In accord with this suggestion, chronic dietary administration of uridine sources to aged rats [78] or to young rats that were subjected to impoverished environment, ameliorated deficits in hippocampaldependent learning and memory [79,80]. Basal and atropineevoked acetylcholine release in brains of freely-moving rats was increased following supplementation with UMP for several weeks [81], perhaps resulting from UDP and UTP stimulation of P2Y receptors. Dietary supplementation with UMP also promoted potassium-evoked dopamine release from rat striatum [82], perhaps indicating a potential therapeutic use for uridine in diseases with brain dopamine deficiency, like Parkinson’s. CONCLUSIONS In conclusion, uridine nucleotides UTP and UDP exhibit numerous biological actions, including extracellular signaling, neuronal differentiation, growth, and neuroprotection apparently mediated by activation of brain P2Y2, P2Y4, and P2Y6 receptors coupled to various intracellular mechanisms. These effects could conceivably underlie new treatments for brain diseases. ACKNOWLEDGEMENTS I thank Dr. Richard J. Wurtman for critical review of this manuscript. I also would like to express my gratitude to Ali Sefa Ekizce for excellent technical support with the figures.

Fig. (2). Kennedy pathway of PC synthesis.

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Involvement of Uridine-Nucleotide-Stimulated P2Y Receptors [76]

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Received: May 29, 2007

Revised: July 07, 2007

Accepted: July 05, 2007

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