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Review

Modulation of the neuronal network activity by P2X receptors and their involvement in neurological disorders F. Sáez-Orellana a , P.A. Godoy a , T. Silva-Grecchi a , K.M. Barra a , J. Fuentealba a,b,∗ a b

Screening of Neuroactive Compounds Unit, Department of Physiology, Faculty of Biological Sciences, Chile Center for Advanced Research on Biomedicine (CIAB-UdeC), University of Concepción, Chile

a r t i c l e

i n f o

Article history: Received 16 June 2015 Received in revised form 18 June 2015 Accepted 18 June 2015 Available online xxx Keywords: Neuromodulation P2X receptors Neurodegeneration Alzheimer’s disease Pore formation

a b s t r a c t ATP is a key energetic molecule, fundamental to cell function, which also has an important role in the extracellular milieu as a signaling molecule, acting as a chemoattractant for immune cells and as a neuroand gliotransmitter. The ionotropic P2X receptors are members of an ATP-gated ion channels family. These ionotropic receptors are widely expressed through the body, with 7 subunits described in mammals, which are arranged in a trimeric configuration with a central pore permeable mainly to Ca2+ and Na+ . All 7 subunits are expressed in different brain areas, being present in neurons and glia. ATP, through these ionotropic receptors, can act as a neuromodulator, facilitating the Ca2+ -dependent release of neurotransmitters, inducing the cross-inhibition between P2XR and GABA receptors, and exercising by this way a modulation of synaptic plasticity. Growing evidence shows that P2XR play an important role in neuronal disorders and neurodegenerative diseases, like Parkinson’s and Alzheimer’s disease; this role involves changes on P2XR expression levels, activation of key pathways like GSK3␤, APP processing, oxidative stress and inflammatory response. This review is focused on the neuromodulatory function of P2XR on pathophysiological conditions of the brain; the recent evidence could open a window to a new therapeutic target. © 2015 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5. 6.

Purinergic receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 P2X receptors distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 P2X receptors and synaptic regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Purinergic receptors and neurodegenerative disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Purinergic receptors and Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Concluding remarks and future direction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Purinergic receptors Adenosine triphosphate (ATP) is a central metabolic and energetic molecule, which also has some roles in the extracellular milieu, acting as a chemoattractant for immune cells and as a neurotransmitter for cells in the central nervous system [1]. The recognition of the role of ATP as a neurotransmitter was pioneered

∗ Corresponding author at: Department of Physiology, University of Concepción, P.O. Box 160-C, Concepción, Chile. Tel.: +56 412661082. E-mail address: [email protected] (J. Fuentealba).

by the work of Holton [2] and largely by the contribution of Burnstock who proposed in 1972, the existence of purinergic nerves [3] and in 1978, the distinction between 2 families of receptors, one activated by adenosine and the other by ATP/ADP denominated P1 and P2, respectively [4]. It was later determined that P2 family was in fact composed by two subtypes of receptors: P2Y, which are G protein-coupled receptors (GPCR), and P2X who belong to the ligand gated ionotropic channel (LGIC) superfamily [5,6]. P2X receptors conform a unique and distinct LGIC family [7], to date 7 subunits have been cloned from mammals, termed P2X1-7 [8]; the subunits are topologically arranged in a short intracellular N-terminus followed by a transmembrane domain (TM1), a large

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extracellular loop with several conserved cysteines, another transmembrane domain (TM2) and finally an intracellular C-terminus of variable length, as depicted in Fig. 1 [9]. Crystallographic studies confirmed that the receptors are arranged in trimers [9,10], which can be homo- or heterotrimers; currently, is accepted that only subunit P2X6 is unable to conform homotrimeric receptor [11], while the most described heterotrimeric receptors are P2X1/2, P2X1/4, P2X1/5, P2X2/3, P2X2/6 and P2X4/6 [11]. These cationic channels have a high relative permeability to Ca2+ compared to Na+ and K+ [12,13]. This high Ca2+ permeability is an important characteristic in order to modulate key neuronal process like exocytosis, mitochondrial function, and pathway signaling. The ion channel is formed by the TM2 segments of each subunit [14] and in the homomeric receptors, the range of sensitivity to ATP, has been described from EC50 = 0.07 ␮M in rat P2X1 to near 100 ␮M in P2X7, also in rat [15]. Physiologically, the release of ATP is finely tuned by 3 mechanisms and involves: vesicle mediated secretion (Ca2+ -dependent) [17], ATP transporters (CFTR, ABC transporters, P-glycoprotein) [18] and channels like connexins or pannexins [19]. The concentration of ATP in the extracellular space has been reported in the range of nano- to micromolar [5]; however millimolar concentrations of ATP could be achieved in the synaptic cleft [19]; reinforcing its role on the synaptic function. Additionally, it has been suggested that a leak in events of cell membrane damage could contribute to extracellular ATP levels, conditioning by this way the synaptic activity [18,20,21]. This last mechanism is important in nociception and some inflammatory pathologies [22], but recently, has been proposed to be part of excitotoxic neurodegenerative mechanisms [21]. The half-life of ATP is estimated in 200 ms [23], being quickly degraded by a complex set of nucleotidases and phosphatases, including ectonucleotide-triphosphatases, phosphodiesterases and ecto-5 -nucleotidase [5,23,24]. In this review, we will focus in how ATP can modulate neural function and the implications of this in the onset and development of neurodegenerative disorders, with special focus on Alzheimer’s disease.

2. P2X receptors distribution Trimeric P2X receptors are assembled in the endoplasmic reticulum (ER), and then trafficked to the cell membrane, this mechanism and the distribution of these receptors is summarized in Fig. 2. The localization of the receptors in the cell depends on the subtype, P2X1 is mainly in the cell surface [25] and studies with chimeric fluorescent receptors demonstrates that the protein is internalized and recycled upon activation [26]. P2X2 is ubiquitous in the neuronal membrane, and low internalization has been observed under sustained ATP stimulation. In parallel, studies with GFP tagged receptors, it has been shown a redistribution of P2X2 at the cell surface of olfactory bulb neurons [27] and also a overexpression on hippocampal embryonic neurons [28]. P2X3 receptors are rapidly internalized upon activation, as observed in HEK293 cells and in neurons from the dorsal horn [29]; interestingly in the same study it was observed that when the receptors were inhibited, they remained in the membrane. Similarly, P2X4 receptors also are internalized upon activation and were trafficked to lysosomes [30]; interestingly, this receptor presents a unique and non-canonical internalization motif [31]. P2X5 and P2X6 are mainly localized in monomeric state in the ER [32]; however, when they heteromerize with P2X2 or P2X4 they can be located at the cell membrane [27]. Finally, P2X7 is distributed mostly in the cell membrane, thanks to its lipid binding sites [33,34], this could be an important element, if we consider that P2X7 has been involved on several pathological conditions on Central Nervous System (CNS) [24]. P2X receptors are widely expressed through the organism, in SNC the 7 subunits are expressed, although with differential levels in distinct area; for example, in some neurons of rat DRG only P2X2 and 3 are expressed [35], while in glia mainly P2X7 is present. However, it is important to note that the level of expression of P2XR depends of the specie, maturational and physiological state, among other consideration; for example, in rat is reported that P2X3 is present in brain from P7 to P14, but not in adult brain [36]; therefore this subject has been already reviewed elsewhere (see [37]).

Fig. 1. P2XR subunit topological arrangement. Subunits are arranged in a short intracellular N-terminus which contains a conserved PKC site with important roles in the modulation of the receptor function [7], two transmembrane domains (TM1 and TM2), a large extracellular loop with several conserved cysteines, important for the allosteric regulation of the receptor [16] and a variable length intracellular C-terminus [9].

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Fig. 2. P2XR intracellular distribution and traffic. The P2X receptors, depending on its conformation characteristics and kinetics, are mostly distributed in the following manners: P2X1 receptors are mainly present at the plasma membrane, and go through fast internalization/recycling processes, mediated by endosomes. P2X2 and P2X7 receptors are assembled at the endoplasmic reticulum and then travel to the plasma membrane where they are highly stable. Due to their slow trafficking to the plasma membrane, these receptors are able to interact with different proteins. P2X3 receptor goes through fast internalization cycles, being mainly located on endosomes and lysosomes, where the receptor is degraded. P2X4 receptors are expressed on the plasma membrane, but mostly on endosomes and lysosomes, since they also go through internalization processes and due to its highly stable nature they resist degradation and are recycled to the plasma membrane. P2X5 receptor is expressed on the plasma membrane when complete, but in humans, the gene that encodes this receptor suffers a deleterious mutation that leaves it in a non-functional state at the endoplasmic reticulum. Homomeric P2X6 receptors are non-functional and located on the endoplasmic reticulum, but when they form heteromeric receptors with P2X2 and P2X4 subunits (P2X2/6 and P2X4/6, respectively), they are mainly expressed on the plasma membrane and have similar behavior to P2X2 and P2X4 receptors.

3. P2X receptors and synaptic regulation All the P2X subunits are expressed in neurons, but their expression is not homogeneous between the distinct brain regions [38], which implies a great variability in their responses to ATP. There are few articles that demonstrate the expression and location of the different subunits at synaptic level, however the presence of the seven subunits in rat hippocampus has been reported in literature [39,40]. Nevertheless, this datum was obtained from a mixed neuronal population, and it is logical to think that in different neuronal subtypes there are different combinations of this receptors, for example, data obtained by single cell RT-PCR demonstrated the expression of P2X1, 2, 3 and 4 in pyramidal neurons from rat hippocampus [39]. The function of the distinct receptors at this level is hard to reveal, mainly due to the vague characterization that has been made of location and expression of the subunits in brain and because of the poor variety of pharmacological tools; although recently this issue has been partially improved utilizing Knockout animals. The use of ATP as a fast neurotransmitter seems to be restricted to the PNS [41], however in certain CNS zones it has been described the use of ATP for inter-neuronal communication, for example in lamina I of dorsal root of spine [42], and even in rat hippocampus CA3 pyramidal neurons [43]; nonetheless this function could be exceptional in CNS, being the principal role of ATP neuromodulation [44], and neuron–glia communication [45]. An example of the involvement of ATP in neuromodulation is given by the observation made by diverse groups at the beginning of the present millennium, when using pharmacological and genetic approaches was possible to establish the involvement of P2X receptors in the formation of LTP in rat hippocampus [46–48]; for instance, in P2X4-KO mice was detected an impairment in LTP formation in hippocampus [49,50], this modification could be due to a reduction in synaptic [Ca2+ ] [50] and related to that, a lower incorporation of NR2B subunits at the post-synapse [49]. Another

interesting aspect to P2X receptors is the capability of interact with other types of receptors, such as nicotinic ␣4␤2 which interacts with P2X2 [41], this provokes a cross-inhibition of both. The most studied interaction is the one involving P2X2 and 4 with different types of GABAA receptors, allowing a modulation of both receptors through cross-inhibition [51,52]. In addition the trafficking of the receptors is inter-depending [53,54] and these two events determine the synaptic efficiency [55]. Besides these post-synaptic effects, it is acknowledged that ATP, via P2X and P2Y can modulate the release of several neurotransmitters such as glutamate [39,56–58], dopamine [59] and GABA [60–62]. This modulation is mainly a facilitation that is mediated by the increase in presynaptic [Ca2+ ], due to the co-release of ATP and the corresponding neurotransmitter. These observations could be relevant when we consider the toxic mechanism of some type of neurodegenerative disease; for example, in the Alzheimer Disease toxic mechanism, the amyloid beta peptide induces in the first stages, a strong excitotoxicity to which ATP likely contributes via synaptic modulation through P2X7 receptors [63–65]. Fig. 3 summarizes some important mechanisms derived from the activation of P2XR at pre-synaptic and post-synaptic levels, on excitatory and inhibitory synapses. Up or down-regulation of these mechanisms could be important on the neurological disorders field of investigation. A third aspect in ATP actions is related to the neuromodulation exerted on neuron–glia communication. In the last 15 years, it has become evident that glia it is not only a support element for neurons, but it is also able to modify the neuronal function and actively participate in processes that before were considered exclusively of the neuron, such as synaptic plasticity; in this aspect it is known that glia possess receptors for most neurotransmitters [66,67], and that the activation of them induces the generation and propagation of a Ca2+ wave, which translates in the release of several molecules from glia, such as NO, glutamate and ATP [66,67]. In the hypothalamus it has been described that glia responds to the release of norepinephrine with a release of ATP at post-synaptic level, which

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Fig. 3. Location of the P2XR at synapses. P2XR are expressed at presynaptic and postsynaptic levels in both excitatory and inhibitory synapses. On both synapses, the influx of Ca2+ to the presynaptic terminal through activated P2XR promotes the liberation of neurotransmitters (like Glutamate and GABA, respectively) and ATP vesicles to the synaptic space. On the excitatory post-synaptic membrane, the activation of P2XR and the subsequent influx of Ca2+ modulate the trafficking of AMPAR vesicles to the cell surface. And on the postsynaptic inhibitory membrane, the activation of P2XR inhibits and down-regulates GABA receptors [21].

is reflected in an increase of [Ca2+ ], the activation of PKC and finally the insertion of AMPA receptors, increasing the response to glutamate in the post-synaptic neuron [68]; additionally, it is described that glia can respond to the release of glutamate and produce a synaptic scaling, increasing the number of glutamate receptors in a bounded region [69]. In the cortex it is known that a synchronization of the neuronal network is required for certain processes, this is denominated UP state [70], the synchronization of the network is dependent of the astrocytes syncytium and specifically of the purinergic signaling between astrocytes [70]. In hippocampus it is described that ATP provokes an inhibition of neuronal network [71], this is mediated by a pre-synaptic inhibition in the release of glutamate [72] and a facilitation in the release of GABA from interneurons [73].

4. Purinergic receptors and neurodegenerative disorders The putative physiological role of P2XR is to facilitate neurotransmitter release; this implies that they could participate in neurological disorders, such as stroke and epilepsy. Furthermore, it is believed that ATP may leave the cells through their plasma membranes when there is damage by mechanical injury or inflammation [19,74]; and this can transform P2XR in important autocrine/paracrine actors in neuropathological conditions [24]. For instance, in the ischemic injury produced during stroke, which is the leading cause of deaths in the US [75]; there is reported an increase in extracellular ATP concentrations [76]. This can mediate the activation of purinergic receptors, and as already stated, P2XR increases the release of glutamate, leading to excitotoxic effects such as increased fEPSC and mEPSC [77,78]. Interestingly the blockade of P2XR with PPADS and suramin reduces the neuronal death induced by the ischemic condition [77,78]. In animal models of ischemia there is an increased expression of P2X2 and 4 which is associated with the extension of the damage [79]. In other injuring processes is described that the increased ATP concentrations activates ERK, promoting cell death [80].

It has been described that ATP is capable of modifying or amplifying the pathophysiological effects of other neurotransmitters [81]. It is widely accepted that hyperactive microglia is crucial for the pathogenesis of several neurodegenerative disorders, and that activated glia is one of the major sources of extracellular ATP [82–84]. All this evidence have led to several studies which suggest that P2X7 receptor contributes to neurodegenerative processes observed in CNS [85]. For example, epilepsy, a neural disorder that affects 50 million people in the world [86], is characterized by a synchronized firing activity of certain brain areas [87], which causes an increase in neurotransmitter levels such as glutamate and ATP [88]. The increase in ATP activates microglia via P2XR [89], and in several models of status epilepticus there is a transient increase in the expression of P2X7 in glutamatergic terminals [90]; furthermore, it has been described that the blockade of P2X7 reduces the duration of seizures and their recurrence [88,91]; besides, in the latent phase of the disease it is reported a diminishment in the expression of P2X4 in GABAergic neurons, which lowers the seizure threshold [90]. On the other hand, adenosine is considered as a natural anticonvulsant, because A1 receptors lower the release of neurotransmitters [88], and therefore, the blockade of P2XR could be a good target for co-adjuvant therapy in refractory epilepsy. In amyotrophic lateral sclerosis (ALS) models it has been reported that ATP increases its concentration as the pathology develops, at low concentration during pre-symptomatic stages prevents the cell death associated with the disease; while at higher concentrations promotes neurotoxicity [92]. Furthermore there is a temporal effect in pre-symptomatic stages P2XR promotes survival of neurons but in symptomatic phase their activation is associated to increased cell death [93]. These differential effects of ATP and P2XR could be associated with different types of receptors, and in literature is reported that at least P2X4 and 7 are involved in the disease [92,94], and this could help to explain the dual effect of ATP in ALS. Both subunits have been found increased in models of the disease and also in samples obtained post mortem from individual who suffered the disease [94–96]. Ivermectin, a drug used for the

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treatment of strongyloidiasis, is a known positive allosteric modulator of P2X4 and it was used in a transgenic model of ALS and in animals it increases life expectancy by 10% [92]. Several authors have demonstrated that P2X7 is associated with a neuroinflammatory condition [5,19,97] and promotes the activation of microglia [98,99]. These features have been observed in ALS, in models of the pathology the use of apyrase (to hydrolyze ATP) [100] or BBG (a non-competitive, blood brain barrier permeable antagonist of P2X7) [93,101], prevented the neuroinflammation observed in animals, delaying the pathogenesis and improving motor performance [93,96,101,102]. These results clearly showed that P2X receptors have a participation in models of ALS, and is necessary more work to translate this to clinical trials to evaluate the potential use of antipurinergic drugs in the pathology, an important challenge for the pharmacology. In Parkison’s Disease (PD), there are reports of increased expression of P2X7 in brain of patients who suffer this disease [103]; and also the presence of a A1513T polymorphism in P2X7 in a Chinese Han population is reported to be a new risk factor for PD [104]. This is in line with results obtained from models of the disease where it is reported that P2X7 is involved in the neuroinflammatory process observed in PD [105,106]. Furthermore, is reported that extracellular ␣-synuclein (␣-syn) co-precipitates with P2X7 in microglia and this interaction is related to the activation of NADPH oxidase via PI3K/AKT that increases the production of ROS, oxidative stress and could lead to increased cell death [107]. Other receptor that appears involved in the pathogenesis of PD is P2X1, the activation of which induces lysosomal dysfunction and accumulation of intracellular ␣-syn and impairment of autophagy [108]. To date this is the only evidence of P2X involvement in PD and more studies are necessary to evaluate the implications of these mechanisms and how they can be used as potential therapeutic targets.

5. Purinergic receptors and Alzheimer’s disease As it has been mentioned previously, several authors have demonstrated that the treatment of cell cultures with A␤ peptide induces an increase in the extracellular ATP concentration [20,109–111], this could allow the activation of purinergic receptors, enhancing the excitotoxic induced by the peptide. In this aspect, researchers have targeted glial activation and the inflammatory component of this disease as a causing agent for neurodegeneration, mainly because purinergic signaling has a key role in the systemic response to injury and inflammation [98,112], and ATP is indicated as a danger signal [113]. In CNS microglia fulfills the role of inflammatory response [98] and therefore most emphasis has been put on the effect of ATP on this cell type over neurons. In literature it is reported that the activation of microglia in AD models depends on P2X7 [114–116], which is found to be overexpressed in the brain of AD diseased persons [115]; in other papers is described that this same receptor is involved in the processing of interleukin-1␤ (IL-1␤) [114,117] which is elevated in the people who suffer of AD [118], and plays a key role in the inflammatory component of it; other authors inhibited this receptor and observed a lower level of gliosis [110] and improvement in behavioral tests in transgenic mice models of the disease [116]. The main inconvenient of these researches is that they imply the release of ATP amounts that allows the activation of P2X7, whose EC50 is more than 100 ␮M and therefore could be related to later stages in the disease. More recently, Delarasse et al. [119], described that the activation of P2X7 promotes the processing of APP using the non-amiloydogenic pathway and it could be a protecting agent for the pathology, this finding was confirmed by another group [120]. The pathway leading to the processing of APP by ␣-secretase was

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analyzed and involves the activation of GSK3␤ [121] and also the phosphorylation of Ezrin/Radixin/Moesin (ERM) [122]. The few articles that are focused in other purinergic receptors have emphasized the action of lower ATP concentrations, but for longer periods of time, for example Canas et al. [123], described that the blockade of A2A receptor, of the P1 family, has a protective effect in animal models of AD. They injected soluble A␤1–42 (2 nM) intraventricularly, and using a specific antagonist for this receptor they observed that these animals did not show any signs of deterioration in their behavior, and presented less histological or cytological markers of neuronal damage, this was confirmed by the use of a KO model. It is important to remark that caffeine is an antagonist of this receptor and there is some evidence that the consumption of moderate doses of coffee can prevent AD [124–126]. Another article published by Varma et al. [127], described that hippocampal cell cultures exposed to A␤1–42 showed an increased expression in P2X4, and the generation of a C-terminus fragment produced by the processing of the receptor by caspase-3; this domain possess molecular determinants important for the internalization of this protein [27,31]. It was also described that the processed receptors showed changes in their electrophysiological properties, such as increased conductance and closing time, increasing the intracellular [Ca2+ ]. As previously commented, permeability of P2X receptors, expressed on neurons, to Ca2+ over monovalent cations (PCa/PM), is high and is around 5 and 12 times, which is comparable to the permeability of NMDAR [12,13], suggesting that ATP could exert a Ca2+ signaling modulation that could induce some synaptotoxicity, similar to glutamatergic excitotoxicity. Interestingly, P2XR receptors are highly permeable to Ca2+ at resting potential, whereas NMDAR are blocked with Mg2+ [13]. Finally, one aspect that has been recently studied in this pathology is the synaptic regulation mediated by P2X, mainly in the release of neurotransmitters [39,56–61]. The presence of these receptors at pre-synaptic level facilitates the release by an increase in cytosolic [Ca2+ ]. In cultures treated with A␤ it has been reported an increase in extracellular [ATP] [20], this can provide a positive feedback mechanism in the A␤ induced excitotoxicity [128]. Recently it has been reported that the blockade of P2XR by PPADS or the hydrolysis of ATP with apyrase show a lower degree of excitotoxicity in a model of AD [21]; in this aspect, is currently recognized that glutamate is an excitotoxic agent [63–65] that induces neurodegeneration via an increased Ca2+ influx and therefore provoking alterations intracellularly. 6. Concluding remarks and future direction The state-of-the-art in P2X neuronal function is that they act as regulators of several processes such as facilitation of neurotransmitter release [59,61], neuronal differentiation and maturation [129,130] and integration with glial network [68–70]. This variety of purinergic signaling allows to a fine tuning and control of neuronal function that can be relevant to design new approaches to understand normal and abnormal brain function, and therefore develop new treatments for diseases like the previously mentioned or even other disorders such as alcoholism [131]. In conclusion, the modulation of P2X receptor and the development of a richer pharmacological arsenal to study these receptors is, under our judgment, a big challenge to help to understand and resolve the toxic mechanism of Alzheimer’s disease and other devastating neurodegenerative disorders. Acknowledgments This work was supported by FONDECYT Iniciación 11090091 (JF), FONDECYT 1130747 (JF).

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References [1] Khakh BS, Burnstock G. The double life of ATP. Sci Am 2009;301(6):84–92. [2] Holton P. The liberation of adenosine triphosphate on antidromic stimulation of sensory nerves. J Physiol 1959;145(3):494–504. [3] Burnstock G. Purinergic nerves. Pharmacol Rev 1972;24(3):509–81. [4] Burnstock G. A basis for distinguishing two types of purinergic receptor. In: Straub RW, Bolis L, editors. Cell Membrane Receptors for Drugs and Hormones: A Multidisciplinary Approach. New York: Raven Press; 1978. p. 107–18. [5] Abbracchio MP, et al. Purinergic signalling in the nervous system: an overview. Trends Neurosci 2009;32(1):19–29. [6] Burnstock G, Kennedy C. Is there a basis for distinguishing two types of P2purinoceptor? Gen Pharmacol 1985;16(5):433–40. [7] North RA. Molecular physiology of P2X receptors. Physiol Rev 2002;82(4):1013–67. [8] Collingridge GL, et al. A nomenclature for ligand-gated ion channels. Neuropharmacology 2009;56(1):2–5. [9] Kawate T, et al. Crystal structure of the ATP-gated P2X4 ion channel in the closed state. Nature 2009;460(7255):592–8. [10] Browne LE, et al. P2X receptor channels show threefold symmetry in ionic charge selectivity and unitary conductance. Nat Neurosci 2011;14(1):17–8. [11] Khakh BS, Alan North R. P2X receptors as cell-surface ATP sensors in health and disease. Nature 2006;442(7102):527–32. [12] Egan TM, Khakh BS. Contribution of calcium ions to P2X channel responses. J Neurosci 2004;24(13):3413–20. [13] Pankratov Y, Lalo U. Calcium permeability of ligand-gated Ca2+ channels. Eur J Pharmacol 2014;15(739):60–73. [14] Egan TM, Haines WR, Voigt MM. A domain contributing to the ion channel of ATP-gated P2X2 receptors identified by the substituted cysteine accessibility method. J Neurosci 1998;18(7):2350–9. [15] Jarvis MF, Khakh BS. ATP-gated P2X cation-channels. Neuropharmacology 2009;56(1):208–15. [16] Coddou C, et al. Activation and regulation of purinergic P2X receptor channels. Pharmacol Rev 2011;63(3):641–83. [17] Pankratov Y, et al. Vesicular release of ATP at central synapses. Pflügers Archiv 2006;452(5):589–97. [18] Franke H, Illes P. Involvement of P2 receptors in the growth and survival of neurons in the CNS. Pharmacol Ther 2006;109(3):297–324. [19] Franke H, Krügel U, Illes P. P2 receptors and neuronal injury. Pflügers Archiv 2006;452(5):622–44. [20] Fuentealba J, et al. Synaptic failure and adenosine triphosphate imbalance induced by amyloid-␤ aggregates are prevented by blueberry-enriched polyphenols extract. J Neurosci Res 2011;89(9):1499–508. [21] Sáez-Orellana F, et al. ATP leakage induces P2XR activation and contributes to acute synaptic excitotoxicity induced by soluble oligomers of ␤-amyloid peptide in hippocampal neurons. Neuropharmacology 2015, http://dx.doi.org/10.1016/j.neuropharm.2015.04.005, pii: S00283908(15)00134-3. [Epub ahead of print]. [22] Cockayne DA, et al. P2X2 knockout mice and P2X2/P2X3 double knockout mice reveal a role for the P2X2 receptor subunit in mediating multiple sensory effects of ATP. J Physiol 2005;567(2):621–39. [23] Benarroch EE. Adenosine triphosphate. Neurology 2010;74(7):601–7. [24] Burnstock G. Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev 2007;87(2):659–797. [25] Lalo U, et al. P2X1 receptor mobility and trafficking; regulation by receptor insertion and activation. J Neurochem 2010;113(5):1177–87. [26] Dutton JL, et al. P2X1 receptor membrane redistribution and down-regulation visualized by using receptor-coupled green fluorescent protein chimeras. Neuropharmacology 2000;39(11):2054–66. [27] Bobanovic LK, Royle SJ, Murrell-Lagnado RD. P2X receptor trafficking in neurons is subunit specific. J Neurosci 2002;22(12):4814–24. [28] Khakh BS, et al. Activation-dependent changes in receptor distribution and dendritic morphology in hippocampal neurons expressing P2X2-green fluorescent protein receptors. Proc Natl Acad Sci U S A 2001;98(9):5288–93. [29] Vacca F, et al. Rapid constitutive and ligand-activated endocytic trafficking of P2X3 receptor. J Neurochem 2009;109(4):1031–41. [30] Xu J, et al. Imaging P2X4 receptor subcellular distribution, trafficking, and regulation using P2X4-pHluorin. J Gen Physiol 2014;144(1):81–104. [31] Royle SJ, et al. Non-canonical YXXG endocytic motifs: recognition by AP2 and preferential utilization in P2X4 receptors. J Cell Sci 2005;118(14):3073–80. [32] Ormond SJ, et al. An uncharged region within the N terminus of the P2X6 receptor inhibits its assembly and exit from the endoplasmic reticulum. Mol Pharmacol 2006;69(5):1692–700. [33] Simons K, Toomre D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 2000;1(1):31–9. [34] Wiley JS, et al. An Ile-568 to Asn polymorphism prevents normal trafficking and function of the human P2X7 receptor. J Biol Chem 2003;278(19):17108–13. [35] Serrano A, et al. Differential expression and pharmacology of native P2X receptors in rat and primate sensory neurons. J Neurosci 2012;32(34):11890–6. [36] Kidd EJ, et al. Evidence for P2X3 receptors in the developing rat brain. Neuroscience 1998;87(3):533–9.

[37] Burnstock G, Dale N. Purinergic signalling during development and ageing. Purinergic Signal 2015:1–29. [38] Majumder P, et al. New insights into purinergic receptor signaling in neuronal differentiation, neuroprotection, and brain disorders. Purinergic Signal 2007;3(4):317–31. [39] Rodrigues RJ, et al. Dual presynaptic control by ATP of glutamate release via facilitatory P2X1, P2X2/3, and P2X3 and inhibitory P2Y1, P2Y2, and/or P2Y4 receptors in the rat hippocampus. J Neurosci 2005;25(27):6286–95. [40] Rubio ME, Soto F. Distinct localization of P2X receptors at excitatory postsynaptic specializations. J Neurosci 2001;21(2):641–53. [41] Khakh BS, et al. An angstrom scale interaction between plasma membrane ATP-gated P2X2 and ␣4␤2 nicotinic channels measured with fluorescence resonance energy transfer and total internal reflection fluorescence microscopy. J Neurosci 2005;25(29):6911–20. [42] Wu JX, et al. Functional up-regulation of P2X3 receptors in dorsal root ganglion in a rat model of bone cancer pain. Eur J Pain 2012;16(10):1378–88. [43] Mori M, et al. Fast synaptic transmission mediated by P2X receptors in CA3 pyramidal cells of rat hippocampal slice cultures. J Physiol 2001;535(1):115–23. [44] Khakh BS, North RA. Neuromodulation by extracellular ATP and P2X receptors in the CNS. Neuron 2012;76(1):51–69. [45] Lalo U, Verkhratsky A, Pankratov Y. Ionotropic ATP receptors in neuronal–glial communication. Semin Cell Dev Biol 2011;22(2):220–8. [46] Fujii S, Kato H, Kuroda Y. Cooperativity between extracellular adenosine 5 -triphosphate and activation of N-methyl-d-aspartate receptors in longterm potentiation induction in hippocampal CA1 neurons. Neuroscience 2002;113(3):617–28. [47] Lorca RA, et al. Zinc enhances long-term potentiation through P2X receptor modulation in the hippocampal CA1 region. Eur J Neurosci 2011;33(7):1175–85. [48] Wang Y, et al. Dual effects of ATP on rat hippocampal synaptic plasticity. Neuroreport 2004;15(4):633–6. [49] Baxter AW, et al. Role of P2X4 receptors in synaptic strengthening in mouse CA1 hippocampal neurons. Eur J Neurosci 2011;34(2):213–20. [50] Sim JA, et al. Altered hippocampal synaptic potentiation in P2X4 knock-out mice. J Neurosci 2006;26(35):9006–9. [51] Boué-Grabot É, et al. Cross-talk and co-trafficking between ␳1/GABA receptors and ATP-gated channels. J Biol Chem 2004;279(8):6967–75. [52] Boué-Grabot É, et al. Subunit-specific coupling between ␥-aminobutyric acid type A and P2X2 receptor channels. J Biol Chem 2004;279(50):52517–25. [53] Kang S, Keasey M, Hagg T. P2X7 receptor inhibition increases CNTF in the subventricular zone, but not neurogenesis or neuroprotection after stroke in adult mice. Transl Stroke Res 2013;4(5):533–45. [54] Shrivastava AN, et al. Regulation of GABAA receptor dynamics by interaction with purinergic P2X2 receptors. J Biol Chem 2011;286(16):14455–68. [55] Jo Y-H, et al. Cross-talk between P2X4 and ␥-aminobutyric acid, type A receptors determines synaptic efficacy at a central synapse. J Biol Chem 2011;286(22):19993–20004. [56] Marcoli M, et al. P2X7 pre-synaptic receptors in adult rat cerebrocortical nerve terminals: a role in ATP-induced glutamate release. J Neurochem 2008;105(6):2330–42. [57] Xing J, Lu J, Li J. Purinergic P2X receptors presynaptically increase glutamatergic synaptic transmission in dorsolateral periaqueductal gray. Brain Res 2008;1208:46–55. [58] Cho J-H, Choi I-S, Jang I-S. P2X7 receptors enhance glutamate release in hippocampal hilar neurons. Neuroreport 2010;21(13):865–70. [59] Choi YM, et al. Modulation of firing activity by ATP in dopamine neurons of the rat substantia nigra pars compacta. Neuroscience 2009;160(3):587–95. [60] Gómez-Villafuertes R, Gualix J, Miras-Portugal MT. Single GABAergic synaptic terminals from rat midbrain exhibit functional P2X and dinucleotide receptors, able to induce GABA secretion. J Neurochem 2001;77(1):84–93. [61] Vavra V, Bhattacharya A, Zemkova H. Facilitation of glutamate and GABA release by P2X receptor activation in supraoptic neurons from freshly isolated rat brain slices. Neuroscience 2011;188:1–12. [62] Xiao C, et al. Purinergic type 2 receptors at GABAergic synapses on ventral tegmental area dopamine neurons are targets for ethanol action. J Pharmacol Exp Ther 2008;327(1):196–205. [63] Lau A, Tymianski M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflügers Archiv 2010;460(2):525–42. [64] Matute C. Glutamate and ATP signalling in white matter pathology. J Anat 2011;219(1):53–64. [65] Mehta A, et al. Excitotoxicity: bridge to various triggers in neurodegenerative disorders. Eur J Pharmacol 2013;698(1–3):6–18. [66] Ben Achour S, Pascual O. Glia: the many ways to modulate synaptic plasticity. Neurochem Int 2010;57(4):440–5. [67] Tasker JG, et al. Glial regulation of neuronal function: from synapse to systems physiology. J Neuroendocrinol 2012;24(4):566–76. [68] Gordon GRJ, et al. Norepinephrine triggers release of glial ATP to increase postsynaptic efficacy. Nat Neurosci 2005;8(8):1078–86. [69] Gordon GRJ, et al. Astrocyte-mediated distributed plasticity at hypothalamic glutamate synapses. Neuron 2009;64(3):391–403. [70] Poskanzer KE, Yuste R. Astrocytic regulation of cortical UP states. Proc Natl Acad Sci U S A 2011;108(45):18453–8. [71] Koizumi S, Inoue K. Inhibition by ATP of calcium oscillations in rat cultured hippocampal neurones. Br J Pharmacol 1997;122(1):51–8.

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[72] Koizumi S, et al. Dynamic inhibition of excitatory synaptic transmission by astrocyte-derived ATP in hippocampal cultures. Proc Natl Acad Sci U S A 2003;100(19):11023–8. [73] Bowser DN, Khakh BS. ATP excites interneurons and astrocytes to increase synaptic inhibition in neuronal networks. J Neurosci 2004;24(39):8606–20. [74] Lazarowski ER, Boucher RC, Harden TK. Constitutive release of ATP and evidence for major contribution of ecto-nucleotide pyrophosphatase and nucleoside diphosphokinase to extracellular nucleotide concentrations. J Biol Chem 2000;275(40):31061–8. [75] Kochanek KD, et al. Deaths: final data for 2009. Natl Vital Stat Rep 2011;60(3):64. [76] Melani A, et al. ATP extracellular concentrations are increased in the rat striatum during in vivo ischemia. Neurochem Int 2005;47(6):442–8. [77] Coppi E, et al. Role of P2 purinergic receptors in synaptic transmission under normoxic and ischaemic conditions in the CA1 region of rat hippocampal slices. Purinergic Signal 2007;3(3):203–19. [78] Zhang Y, et al. Enhancement of excitatory synaptic transmission in spiny neurons after transient forebrain ischemia. J Neurophysiol 2006;95(3): 1537–44. [79] Cavaliere F, et al. Up-regulation of P2X2, P2X4 receptor and ischemic cell death: prevention by P2 antagonists. Neuroscience 2003;120(1):85–98. [80] Neary JT, et al. Activation of extracellular signal-regulated kinase by stretchinduced injury in astrocytes involves extracellular ATP and P2 purinergic receptors. J Neurosci 2003;23(6):2348–56. [81] Apolloni S, et al. Membrane compartments and purinergic signalling: P2X receptors in neurodegenerative and neuroinflammatory events. FEBS J 2009;276(2):354–64. [82] Amadio S, et al. Differences in the neurotoxicity profile induced by ATP and ATPgS in cultured cerebellar granule neurons. Neurochem Int 2005;47(5):334–42. [83] Amadio S, et al. P2 receptor modulation and cytotoxic function in cultured CNS neurons. Neuropharmacology 2002;42(4):489–501. [84] Köles L, et al. Interaction of P2 purinergic receptors with cellular macromolecules. Naunyn-Schmiedeberg’s Arch Pharmacol 2008;377(1):1–33. [85] Kaczmarek-Hájek K, et al. Molecular and functional properties of P2X receptors – recent progress and persisting challenges. Purinergic Signal 2012: 1–43. [86] Savage N. Epidemiology: the complexities of epilepsy. Nature 2014;511(7508):S2–3. [87] Fisher RS, et al. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 2005;46(4):470–2. [88] Klaft Z-J, et al. Extracellular ATP differentially affects epileptiform activity via purinergic P2X7 and adenosine A1 receptors in naive and chronic epileptic rats. Epilepsia 2012;53(11):1978–86. [89] Avignone E, et al. Status epilepticus induces a particular microglial activation state characterized by enhanced purinergic signaling. J Neurosci 2008;28(37):9133–44. [90] Doná F, et al. Alteration of purinergic P2X4 and P2X7 receptor expression in rats with temporal-lobe epilepsy induced by pilocarpine. Epilepsy Res 2009;83(2–3):157–67. [91] Engel T, et al. Seizure suppression and neuroprotection by targeting the purinergic P2X7 receptor during status epilepticus in mice. FASEB J 2012;26(4):1616–28. [92] Andries M, et al. Ivermectin inhibits AMPA receptor-mediated excitotoxicity in cultured motor neurons and extends the life span of a transgenic mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 2007;25(1):8–16. [93] Apolloni S, et al. Spinal cord pathology is ameliorated by P2X7 antagonism in a SOD1-mutant mouse model of amyotrophic lateral sclerosis. Dis Models Mech 2014;7(9):1101–9. [94] D’Ambrosi N, et al. The proinflammatory action of microglial p2 receptors is enhanced in SOD1 models for amyotrophic lateral sclerosis. J Immunol 2009;183(7):4648–56. [95] Casanovas A, et al. Strong P2X4 purinergic receptor-like immunoreactivity is selectively associated with degenerating neurons in transgenic rodent models of amyotrophic lateral sclerosis. J Comp Neurol 2008;506(1):75–92. [96] Yiangou Y, et al. COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. BMC Neurol 2006;6(1):12. [97] Fields RD. Nonsynaptic and nonvesicular ATP release from neurons and relevance to neuron–glia signaling. Semin Cell Dev Biol 2011;22(2):214–9. [98] Di Virgilio F, et al. Purinergic signalling in inflammation of the central nervous system. Trends Neurosci 2009;32(2):79–87. [99] Skaper SD, et al. P2X7 receptors on microglial cells mediate injury to cortical neurons in vitro. Glia 2006;54(3):234–42. [100] Gandelman M, et al. Extracellular ATP and the P2X7 receptor in astrocytemediated motor neuron death: implications for amyotrophic lateral sclerosis. J Neuroinflammation 2010;7(1):33. [101] Cervetto C, et al. Motor neuron dysfunction in a mouse model of ALS: genderdependent effect of P2X7 antagonism. Toxicology 2013;311(1–2):69–77.

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[102] Parisi C, et al. Dysregulated microRNAs in amyotrophic lateral sclerosis microglia modulate genes linked to neuroinflammation. Cell Death Dis 2013;4:e959. [103] Durrenberger PF, et al. Inflammatory pathways in Parkinson’s disease: a BNE microarray study. Parkinson’s Dis 2012;2012:16. [104] Liu H, et al. Association of P2X7 receptor gene polymorphisms with sporadic Parkinson’s disease in a Han Chinese population. Neurosci Lett 2013;546:42–5. [105] Marcellino D, et al. On the role of P2X7 receptors in dopamine nerve cell degeneration in a rat model of Parkinson’s disease: studies with the P2X7 receptor antagonist A-438079. J Neural Transm 2010;117(6):681–7. [106] Jun D-J, et al. Extracellular ATP mediates necrotic cell swelling in SN4741 dopaminergic neurons through P2X7 receptors. J Biol Chem 2007;282(52):37350–8. [107] Jiang T, et al. P2X7 receptor is critical in ␣-synuclein-mediated microglial NADPH oxidase activation. Neurobiol Aging 2015;36(7):2304–18. [108] Gan M, et al., Extracellular ATP. induces intracellular alpha-synuclein accumulation via P2X1 receptor-mediated lysosomal dysfunction. Neurobiol Aging 2015;36(2):1209–20. [109] Kim SY, et al. ATP released from ␤-amyloid-stimulated microglia induces reactive oxygen species production in an autocrine fashion. Exp Mol Med 2007;39(6):820–7. [110] Ryu JK, McLarnon JG. Block of purinergic P2X7 receptor is neuroprotective in an animal model of Alzheimer’s disease. Neuroreport 2008;19(17):1715–9. [111] Sanz JM, et al. Activation of microglia by amyloid ␤ requires P2X7 receptor expression. J Immunol 2009;182(7):4378–85. [112] Mei L, et al. Purinergic signaling: a novel mechanism in immune surveillance. Acta Pharmacol Sin 2010;31(9):1149–53. [113] Trautmann A. Extracellular ATP in the immune system: more than just a “danger signal”. Sci Signal 2009;2(56):pe6. [114] Choi HB, et al. Modulation of the purinergic P2X7 receptor attenuates lipopolysaccharide-mediated microglial activation and neuronal damage in inflamed brain. J Neurosci 2007;27(18):4957–68. [115] McLarnon JG, et al. Upregulated expression of purinergic P2X7 receptor in Alzheimer disease and amyloid-␤ peptide-treated microglia and in peptideinjected rat hippocampus. J Neuropathol Exp Neurol 2006;65(11):1090–7. [116] Parvathenani LK, et al. P2X7 mediates superoxide production in primary microglia and is up-regulated in a transgenic mouse model of Alzheimer’s disease. J Biol Chem 2003;278(15):13309–17. [117] Csölle C, Sperlágh B. Peripheral origin of IL-1b production in the rodent hippocampus under in vivo systemic bacterial lipopolysaccharide (LPS) challenge and its regulation by P2X7 receptors. J Neuroimmunol 2010;219(1–2):38–46. [118] Licastro F, et al. Increased plasma levels of interleukin-1, interleukin-6 and ␣1-antichymotrypsin in patients with Alzheimer’s disease: peripheral inflammation or signals from the brain? J Neuroimmunol 2000;103(1):97–102. [119] Delarasse C, et al. The purinergic receptor P2X7 triggers ␣-secretasedependent processing of the amyloid precursor protein. J Biol Chem 2011;286(4):2596–606. [120] León-Otegui M, et al. Opposite effects of P2X7 and P2Y2 nucleotide receptors on ␣-secretase-dependent APP processing in Neuro-2a cells. FEBS Lett 2011;585(14):2255–62. [121] Diaz-Hernandez JI, et al. In vivo P2X7 inhibition reduces amyloid plaques in Alzheimer’s disease through GSK3␤ and secretases. Neurobiol Aging 2012;33(8):1816–28. [122] Darmellah A, et al. Ezrin/radixin/moesin are required for the purinergic P2X7 receptor (P2X7R)-dependent processing of the amyloid precursor protein. J Biol Chem 2012;287(41):34583–95. [123] Canas PM, et al. Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by ␤-amyloid peptides via p38 mitogenactivated protein kinase pathway. J Neurosci 2009;29(47):14741–51. [124] Ritchie K, et al. The neuroprotective effects of caffeine: a prospective population study (the Three City Study). Neurology 2007;69(6):536–45. [125] Eskelinen MH, Kivipelto M. Caffeine as a protective factor in dementia and Alzheimer’s disease. J Alzheimer’s Dis 2010;20:167–74. [126] Carman AJ, et al. Current evidence for the use of coffee and caffeine to prevent age-related cognitive decline and Alzheimer’s disease. J Nutr Health Aging 2014;18(4):383–92. [127] Varma R, et al. Amyloid-␤ induces a caspase-mediated cleavage of P2X4 to promote purinotoxicity. Neuromol Med 2009;11(2):63–75. [128] Parodi J, et al. ␤-Amyloid causes depletion of synaptic vesicles leading to neurotransmission failure. J Biol Chem 2010;285(4):2506–14. [129] Schwindt T, et al. Directed differentiation of neural progenitors into neurons is accompanied by altered expression of P2X purinergic receptors. J Mol Neurosci 2011;44(3):141–6. [130] Yuahasi KK, et al. Regulation of neurogenesis and gliogenesis of retinoic acidinduced P19 embryonal carcinoma cells by P2X2 and P2X7 receptors studied by RNA interference. Int J Dev Neurosci 2012;30(2):91–7. [131] Asatryan L, et al. Roles of ectodomain and transmembrane regions in ethanol and agonist action in purinergic P2X2 and P2X3 receptors. Neuropharmacology 2008;55(5):835–43.

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Modulation of the neuronal network activity by P2X receptors and their involvement in neurological disorders.

ATP is a key energetic molecule, fundamental to cell function, which also has an important role in the extracellular milieu as a signaling molecule, a...
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