P2 receptor web: Complexity and fine-tuning
Introduction
Extracellular nucleoside tri- and diphosphates, first of which the prototype ATP, are considered as the phylogenetically most ancient epigenetic factors sustaining a broad range of short-term and long-term biological effects. In several different tissues, these can vary from neurotransmission, smooth and cardiac muscle contraction, chemosensory signaling, secretion, vasodilatation, microglia activation, to more complex phenomena such as immune responses, male reproduction, fertilization and embryonic development (Burnstock & Knight, 2004, Illes & Ribeiro, 2004, Vial et al., 2004a, Burnstock, 2006a, Burnstock, 2006b, Burnstock, 2006c, Burnstock, 2006d). Effects as different as proliferation, differentiation, chemotaxis, release of cytokines or lysosomal constituents, generation of reactive oxygen or nitrogen species, are moreover elicited by extracellular ATP upon stimulation of blood cells. In addition to these well-described physiological activities, extracellular nucleotides are also recognized as having increasing importance in pathological conditions (Burnstock, 2004a, Gallagher, 2004, Cattaneo, 2005, Kennedy, 2005, Burnstock, 2006a). They have key roles in cancer, cardiopulmonary insufficiency, thrombosis, diabetes, skin and bone diseases, gut motility disorders, diseases of the ear and eye, bladder incontinence, behavioral disorders and pain (James & Butt, 2002, D'Ambrosi et al., 2004, Di Virgilio et al., 2005, White et al., 2005, Burnstock, 2006b). Particularly in the central nervous system (CNS), in addition to their established functions as neurotransmitters, cotransmitters, neuromodulators and growth factors (Burnstock, 2004b), extracellular nucleotides have recently been shown to have additional biological tasks ranging from survival, repair, remodeling during development, to involvement in injury, metabolism impairment, excitotoxicity, acute and chronic neurodegenerative conditions (Volonté et al., 2003, Franke & Illes, 2006). They participate in neuronal mechanisms triggered by axotomy in rat precerebellar nuclei (Florenzano et al., 2002), in astrocytic effects induced by stab wounds (Franke et al., 2004a), in reactive gliosis occurring after traumatic brain injury (Neary et al., 2005), in neuronal and glial responses to cerebral ischemia in vitro and in vivo (Cavaliere et al., 2002, Cavaliere et al., 2004a, Franke et al., 2004b, Melani et al., in press) and in neuronal recovery after growth factor withdrawal (D'Ambrosi et al., 2000, D'Ambrosi et al., 2001). It is well known that metabolic stress, brain ischemia and trauma often evoke massive extracellular release of ATP and additional excitotoxic neurotransmitters (Phillis et al., 1993, Juranyi et al., 1999, Melani et al., 2005), and extracellular ATP per se is noxious to primary CNS neurons (Amadio et al., 2002, Amadio et al., 2005). Also it mediates hypoxic/hypoglycemic signaling in vitro (Cavaliere et al., 2001a, Cavaliere et al., 2001b, Cavaliere et al., 2002, Cavaliere et al., 2004a, Cavaliere et al., 2004b) and in vivo (Prasad et al., 2001, Cavaliere et al., 2003, Franke et al., 2004b). Consistent with this, several purinergic antagonists abolish the cell death fate of primary neurons exposed to excessive glutamate (Volonté & Merlo, 1996), serum/potassium deprivation (Volonté et al., 1999), hypoglycemia and chemical hypoxia (Cavaliere et al., 2001a, Cavaliere et al., 2001b, Cavaliere et al., 2002, Cavaliere et al., 2004a, Cavaliere et al., 2004b). Nevertheless, ATP released from cells (Neary et al., 1996, Bodin & Burnstock, 2001) acts not only on neurons, but also mediates microglial inflammatory processes involved either in pathological conditions, or in the protection of the CNS (Kreutzberg, 1996, Minghetti et al., 1999). For instance, ATP is a trigger for tumour necrosis factor-α secretion and a modulator for interleukin-1β release from cultured microglia, suggesting that outflow of ATP during degenerative events could also boost the pro-inflammatory response of already activated microglial cells (Di Virgilio et al., 1998, Di Virgilio et al., 2001). All these functions substantiate the high level of complexity of purinergic mechanisms.
Section snippets
Molecular and pharmacological classification
As expected in sustaining so many sophisticated biological tasks, the specific extracellular receptors for nucleoside tri/diphosphates, the P2 receptors, show heterogeneity at the molecular level. They are subdivided into ionotropic ATP-gated ion channels (P2X receptors), mediating rapid and selective permeability to Na+, K+ and Ca2+ (North, 2002) and into G protein-coupled metabotropic subtypes (P2Y receptors), inducing a slower onset of responses and involving second-messenger systems (
P2 receptor localization
The biological complexity and heterogeneity of P2 receptors (Fig. 1, Fig. 2) is not uniquely of a molecular and pharmacological nature, as described above, but is further accomplished at a cellular and subcellular level.
Subunit association and receptor cross talk
The biological complexity of P2 receptors is further augmented, if we consider that both P2X and P2Y subtypes can form homomers and heteromers (Torres et al., 1999, Nakata et al., 2004), and that the composition of the oligomers profoundly affects the biological response of these receptors. Different subtype combinations thus yields different receptor characteristics, allowing increasing diversities in agonist and antagonist selectivity, transmission signaling, channel and desensitization
P2 receptor web and fine-tuning
Some P2 receptor subtypes are very similar, others have quite different properties. For instance, P2Y12 and P2Y13 receptors have the same preference for endogenous agonists (particularly ADP) and couple to the same intracellular signal transduction pathway, hence implicating on a first analysis that cellular responses might be analogous, whether a cell expresses one or the other receptor subtype (or a mixture of both). Moreover, P2Y1 receptors are coupled to stimulation of nitric oxide
Concluding remarks
We propose here the new model of “combinatorial receptor web and fine-tuning” to unravel the complexity of P2 receptors, with the goal of enquiring what ultimately distinguishes this receptor intricacy. Nevertheless, this same intricacy is the most amazing feature of P2 receptors, because of the way in which fundamental building blocks, the P2 proteins, are recruited in an ordered way on a single cell, with even more complexity reached during physiopathological conditions. We do hope that
Acknowledgments
We are most grateful to Prof. Giorgio Bernardi for encouraging our work, to Dr. Fabio Cavaliere, Dr. Fabrizio Vacca for key experiments which inspired this review, and to Dr. Gillian E. Knight for her excellent editorial skills. The present work was supported in part by Cofinanziamenti MIUR.
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2021, Journal of Oral BiosciencesCitation Excerpt :The IL-6-producing ability may also affect the different effects of adenine nucleotides between each OSCC cell line. Physiological P2R agonists activate multiple P2Rs that are expressed in a single cell; therefore, multiple P2Rs are coordinately involved in stimulation by adenine nucleotides [31]. The pan-P2R antagonist suramin and P2XR antagonist Evans blue inhibited IL-6 production by HSC-2 cells stimulated with ATP or ADP, indicating the involvement of P2Rs.
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2019, Seminars in Cell and Developmental BiologyCitation Excerpt :The extracellular concentration of purines and pyrimidines is generally low in healthy tissue, but it rises at sites of stress, damage and cell injury, leading to stimulation of purinergic receptors. The role of extracellular ATP in the neurodegeneration of the nervous system has been established a long ago [40,41]. Indeed, among the several factors released during acute and chronic pathologies, extracellular purines and pyrimidines act as modulators of neurodegeneration and neuroinflammation, by targeting several different cell phenotypes in the CNS [42–46].
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2017, Advances in ImmunologyCitation Excerpt :Further, purine nucleotide derivatives such as NAD + have been identified as agonists on the P2Y11 (Moreschi et al., 2006). However, the set of endogenous ligands interacting with P2Y receptor seems to be even more complex, suggesting network-modulating and fine-tuning nucleotide receptors (Volonte, Amadio, D'Ambrosi, Colpi, & Burnstock, 2006). As shown in Fig. 1, P2Y receptors cluster in the δ subfamily of rhodopsin-like GPCR together with leukotriene, lipid, and short fatty acid metabolite receptors (Fredriksson, Lagerstrom, Lundin, & Schioth, 2003).
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2016, NeuropharmacologyCitation Excerpt :Among these, in this special issue on “Purinergic signalling in neurodegeneration and neuroregeneration”, we will focus particularly on amyotrophic lateral sclerosis (ALS), a disease that arises from complications in the lateral corticospinal tract, with deleterious consequences on upper and lower motoneurons respectively in brain stem and ventral horns of spinal cord, and mainly on lumbar motoneurons (Paez-Colasante et al., 2015). By reviewing the most recent literature on purinergic signalling in ALS, and outlining a novel identification of P2 receptors as potential markers for the disease, we will challenge the concept that a dynamic and cooperative architecture of purinergic receptors (Volonté et al., 2008a, 2006; Volonté and D'Ambrosi, 2009) might become relevant also in the pathological context of ALS. While being at least two century-old (Table 1), ALS is classified as a rare disease, even if it is the most common motoneuron disease, affecting people of all races and ethnic backgrounds.