ATP: a ubiquitous gliotransmitter integrating neuron-glial networks

Astrocytes are ideally situated to integrate glial and neuronal functions and neurovascular coupling by way of their multiple contacts with neurons, glia and blood vessels. There is a high degree of specialisation of astroglial membranes at the different sites of contact, including the expression of neurotransmitter receptors, ion channels, transporters and gap junctional proteins. An apparently universal property of astrocytes throughout the CNS is their responsiveness to ATP acting via metabotropic P2Y receptors, with a prominent role for the P2Y1 receptor subtype. Activation of astroglial P2Y receptors triggers a rise in intracellular calcium, which is the substrate for astroglial excitability and intercellular communication. In addition, astrocytes have a number of mechanisms for the release of ATP, which can be considered a 'gliotransmitter'. Astrocytes may be the most widespread source of ATP release in the CNS, and astroglial ATP and its metabolite adenosine activate purine receptors on neurons, microglia, oligodendrocytes and blood vessels. There is compelling evidence that astroglial ATP and adenosine regulate neuronal synaptic strength, although the physiological significance of this astrocyte-to-neuron signalling is questioned. A less appreciated aspect of astrocyte signalling is that they also release neurotransmitters onto other glia. Notably, both ATP and adenosine control microglial behaviour and regulate oligodendrocyte differentiation and myelination. P2 receptors also mediate injury responses in all glial cell types, with a prominent role for the P2X7 receptor subtype. In addition, ATP is a potent vasoconstrictor and astrocytes provide a route for coupling blood flow to neuronal activity by way of their synaptic and perivascular connections. Thus, astrocytes are the fulcrum of neuron-glial-vascular networks and purinergic signalling is the primary mechanism by which astrocytes can integrate the functions of these diverse elements.     

Stimulation of Glia Reveals Modulation of Mammalian Spinal Motor Networks by Adenosine

Despite considerable evidence that glia can release modulators to influence the excitability of neighbouring neurons, the importance of gliotransmission for the operation of neural networks and in shaping behaviour remains controversial. Here we characterise the contribution of glia to the modulation of the mammalian spinal central pattern generator for locomotion, the output of which is directly relatable to a defined behaviour. Glia were stimulated by specific activation of protease-activated receptor-1 (PAR1), an endogenous G-protein coupled receptor preferentially expressed by spinal glia during ongoing activity of the spinal central pattern generator for locomotion. Selective activation of PAR1 by the agonist TFLLR resulted in a reversible reduction in the frequency of locomotor-related bursting recorded from ventral roots of spinal cord preparations isolated from neonatal mice. In the presence of the gliotoxins methionine sulfoximine or fluoroacetate, TFLLR had no effect, confirming the specificity of PAR1 activation to glia. The modulation of burst frequency upon PAR1 activation was blocked by the non-selective adenosine-receptor antagonist theophylline and by the A₁-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, but not by the A_2A-receptor antagonist SCH5826, indicating production of extracellular adenosine upon glial stimulation, followed by A₁-receptor mediated inhibition of neuronal activity. Modulation of network output following glial stimulation was also blocked by the ectonucleotidase inhibitor ARL67156, indicating glial release of ATP and its subsequent degradation to adenosine rather than direct release of adenosine. Glial stimulation had no effect on rhythmic activity recorded following blockade of inhibitory transmission, suggesting that glial cell-derived adenosine acts via inhibitory circuit components to modulate locomotor-related output. Finally, the modulation of network output by endogenous adenosine was found to scale with the frequency of network activity, implying activity-dependent release of adenosine. Together, these data indicate that glia play an active role in the modulation of mammalian locomotor networks, providing negative feedback control that may stabilise network activity.     

Neuroprotective roles of the P2Y2 receptor

Purinergic signaling plays a unique role in the brain by integrating neuronal and glial cellular circuits. The metabotropic P1 adenosine receptors and P2Y nucleotide receptors and ionotropic P2X receptors control numerous physiological functions of neuronal and glial cells and have been implicated in a wide variety of neuropathologies. Emerging research suggests that purinergic receptor interactions between cells of the central nervous system (CNS) have relevance in the prevention and attenuation of neurodegenerative diseases resulting from chronic inflammation. CNS responses to chronic inflammation are largely dependent on interactions between different cell types (i.e., neurons and glia) and activation of signaling molecules including P2X and P2Y receptors. Whereas numerous P2 receptors contribute to functions of the CNS, the P2Y(2) receptor is believed to play an important role in neuroprotection under inflammatory conditions. While acute inflammation is necessary for tissue repair due to injury, chronic inflammation contributes to neurodegeneration in Alzheimer's disease and occurs when glial cells undergo prolonged activation resulting in extended release of proinflammatory cytokines and nucleotides. This review describes cell-specific and tissue-integrated functions of P2 receptors in the CNS with an emphasis on P2Y(2) receptor signaling pathways in neurons, glia, and endothelium and their role in neuroprotection.     

Extracellular nucleotide signaling in the inner ear

Extracellular nucleotides, particularly adenosine 5′-triphosphate (ATP), act as signaling molecules in the inner ear. Roles as neurotransmitters, neuromodulators, and as autocrine or paracrine humoral factors are evident. The diversity of the signaling pathways for nucleotides, which include a variety of ATP-gated ion channels (assembled from different subtypes of P2X-receptor subunit) and also different subtypes of G protein-coupled nucleotide receptors (P2Y receptors) supports a major physiological role for ATP in the regulation of hearing and balance. Almost invariably both P2X and P2Y receptor expression is apparent in the complex tissue structures associated with the inner-ear labyrinth. However P2X-receptor expression, commonly associated with fast neurotransmission, is apparent not only with the cochlear and vestibular primary afferent neurons, but also appears to mediate humoral signaling via ATP-gated ion channel localization to the endolymphatic surface of the cochlear sensory epithelium (organ of Corti). This is the site of the sound-transduction process and recent data, including both electrophysiological, imaging, and immunocytochemistry, has shown that the ATP-gated ion channels are colocalized here with the mechano-electrical transduction channels of the cochlear hair cells. In contrast to this direct action of extracellular ATP on the sound-transduction process, an indirect effect is apparent via P2Y-receptor expression, prevalent on the marginal cells of the stria vascularis, a tissue that generates the standing ionic and electrical gradients across the cochlear partition. The site of generation of these gradients, including the dark-cell epithelium of the vestibular labyrinth, may be under autocrine or paracrine regulation mediated by P2Y receptors sensitive to both purines (ATP) and pyrimidines such as UTP. There is also emerging evidence that the nucleoside adenosine, formed as a breakdown product of ATP by the action of ectonucleotidases and acting via P1 receptors, is also physiologically significant in the inner ear. P1-receptor expression (including A₁, A₂, and A₃ subtypes) appear to have roles associated with stress, acting alongside P2Y receptors to enhance cochlear blood flow and to protect against the action of free radicals and to modulate the activity of membrane conductances. Given the positioning of a diverse range of purinergic-signaling pathways within the inner ear, elevations of nucleotides and nucleosides are clearly positioned to affect hearing and balance. Recent data clearly supports endogenous ATP- and adenosine-mediated changes in sensory transduction via a regulation of the electrochemical gradients in the cochlea, alterations in the active and passive mechanical properties of the cells of the sensory epithelium, effects on primary afferent neurons, and control of the blood supply. The field now awaits conclusive evidence linking a physiologically-induced modulation of extracellular nucleotide and nucleoside levels to altered inner ear function.     

Astrocytes Protect Neurons against Methylmercury via ATP/P2Y1 Receptor-Mediated Pathways in Astrocytes

Methylmercury (MeHg) is a well known environmental pollutant that induces serious neuronal damage. Although MeHg readily crosses the blood-brain barrier, and should affect both neurons and glial cells, how it affects glia or neuron-to-glia interactions has received only limited attention. Here, we report that MeHg triggers ATP/P2Y₁ receptor signals in astrocytes, thereby protecting neurons against MeHg via interleukin-6 (IL-6)-mediated pathways. MeHg increased several mRNAs in astrocytes, among which IL-6 was the highest. For this, ATP/P2Y₁ receptor-mediated mechanisms were required because the IL-6 production was (i) inhibited by a P2Y₁ receptor antagonist, MRS2179, (ii) abolished in astrocytes obtained from P2Y₁ receptor-knockout mice, and (iii) mimicked by exogenously applied ATP. In addition, (iv) MeHg released ATP by exocytosis from astrocytes. As for the intracellular mechanisms responsible for IL-6 production, p38 MAP kinase was involved. MeHg-treated astrocyte-conditioned medium (ACM) showed neuro-protective effects against MeHg, which was blocked by anti-IL-6 antibody and was mimicked by the application of recombinant IL-6. As for the mechanism of neuro-protection by IL-6, an adenosine A₁ receptor-mediated pathway in neurons seems to be involved. Taken together, when astrocytes sense MeHg, they release ATP that autostimulates P2Y₁ receptors to upregulate IL-6, thereby leading to A₁ receptor-mediated neuro-protection against MeHg.     

The Role of Glial Adenosine Receptors in Neural Resilience and the Neurobiology of Mood Disorders

Adenosine receptors were classified into A₁- and A₂-receptors in the laboratory of Bernd Hamprecht more than 25 years ago. Adenosine receptors are instrumental to the neurotrophic effects of glia cells. Both microglia and astrocytes release after stimulation via adenosine receptors factors that are important for neuronal survival and growth. Neuronal resilience is now considered as of pivotal importance in the neurobiology of mood disorders and their treatment. Both sleep deprivation and electroconvulsive therapy, two effective therapeutic measures in mood disorders, are associated with an increase of adenosine and upregulation of adenosine A₁-receptors in the brain. Parameters closely related to adenosine receptor activation such as cerebral metabolic rate and delta power in the sleep EEG provide indirect evidence that adenosinergic signaling may be associated with the therapeutic response to these measures. Thus, neurotrophic effects evoked by adenosine receptors might be important in the mechanism of action of ECT and perhaps also sleep deprivation.     

Roles of P2 receptors in glial cells: focus on astrocytes

Central nervous system glial cells release and respond to nucleotides under both physiological and pathological conditions, suggesting that these molecules play key roles in both normal brain function and in repair after damage. In particular, ATP released from astrocytes activates P2 receptors on astrocytes and other brain cells, allowing a form of homotypic and heterotypic signalling, which also involves microglia, neurons and oligodendrocytes. Multiple P2X and P2Y receptors are expressed by both astrocytes and microglia; however, these receptors are differentially recruited by nucleotides, depending upon specific pathophysiological conditions, and also mediate the long-term trophic changes of these cells during inflammatory gliosis. In astrocytes, P2-receptor-induced gliosis occurs via activation of the extracellular-regulated kinases (ERK) and protein kinase B/Akt pathways and involves induction of inflammatory and anti-inflammatory genes, cyclins, adhesion and antiapoptotic molecules. While astrocytic P2Y₁ and P2Y_2,4 are primarily involved in short-term calcium-dependent signalling, multiple P2 receptor subtypes seem to cooperate to astrocytic long-term changes. Conversely, in microglia, exposure to inflammatory and immunological stimuli results in differential functional changes of distinct P2 receptors, suggesting highly specific roles in acquisition of the activated phenotype. We believe that nucleotide-induced activation of astrocytes and microglia may originally start as a defence mechanism to protect neurons from cytotoxic and ischaemic insults; dysregulation of this process in chronic inflammatory diseases eventually results in neuronal cell damage and loss. On this basis, full elucidation of the specific roles of P2 receptors in these cells may help exploit the beneficial neuroprotective features of activated glia while attenuating their harmful properties and thus provide the basis for novel neuroprotective strategies that specifically target the purinergic system.     

ATP released by astrocytes mediates glutamatergic activity-dependent heterosynaptic suppression

Extracellular ATP released from axons is known to assist activity-dependent signaling between neurons and Schwann cells in the peripheral nervous system. Here we report that ATP released from astrocytes as a result of neuronal activity can also modulate central synaptic transmission. In cultures of hippocampal neurons, endogenously released ATP tonically suppresses glutamatergic synapses via presynaptic P2Y receptors, an effect that depends on the presence of cocultured astrocytes. Glutamate release accompanying neuronal activity also activates non-NMDA receptors of nearby astrocytes and triggers ATP release from these cells, which in turn causes homo- and heterosynaptic suppression. In CA1 pyramidal neurons of hippocampal slices, a similar synaptic suppression was also produced by adenosine, an immediate degradation product of ATP released by glial cells. Thus, neuron-glia crosstalk may participate in activity-dependent synaptic modulation.     

克隆的P2受体亚型的药理学研究进展

细胞外嘌呤（腺苷,ADP,ATP）及嘧啶（UDP,UTP）为重要的信使分子,通过细胞表面P2受体介导产生不同的生物效应,P2嘌吟受体的概念于1978年被提出,随后根据药理学特征又被分为P2X及P2X嘌呤受体,90年代,采用分子生物学手段,一系列配体门控的P2X受体及G蛋白耦联的P2Y受体被克隆及功能表达,迄今为止,已有七型P2X受体亚型（P2X1－7）及六型P2Y受体亚型被克隆（P2Y1,2,4,6,11,12）,各型具有不同的分子结构,药理学特征及组织分布,本文还讨论了目前可用于区分各亚型激动剂及拮抗剂。     

Role of purinergic receptors in the Alzheimer’s disease

Etiology of the Alzheimer’s disease (AD) is not fully understood. Different pathological processes are considered, such as amyloid deposition, tau protein phosphorylation, oxidative stress (OS), metal ion disregulation, or chronic neuroinflammation. Purinergic signaling is involved in all these processes, suggesting the importance of nucleotide receptors (P2X and P2Y) and adenosine receptors (A1, A2A, A2B, A3) present on the CNS cells. Ecto-purines, ecto-pyrimidines, and enzymes participating in their metabolism are present in the inter-cellular spaces. Accumulation of amyloid-β (Aβ) in brain induces the ATP release into the extra-cellular space, which in turn stimulates the P2X7 receptors. Activation of P2X7 results in the increased synthesis and release of many pro-inflammatory mediators such as cytokines and chemokines. Furthermore, activation of P2X7 leads to the decreased activity of α-secretase, while activation of P2Y2 receptor has an opposite effect. Simultaneous inhibition of P2X7 and stimulation of P2Y2 would therefore be the efficient way of the α-secretase activation. Activation of P2Y2 receptors present in neurons, glia cells, and endothelial cells may have a positive neuroprotective effect in AD. The OS may also be counteracted via the purinergic signaling. ADP and its non-hydrolysable analogs activate P2Y13 receptors, leading to the increased activity of heme oxygenase, which has a cytoprotective activity. Adenosine, via A1 and A2A receptors, affects the dopaminergic and glutaminergic signaling, the brain-derived neurotrophic factor (BNDF), and also changes the synaptic plasticity (e.g., causing a prolonged excitation or inhibition) in brain regions responsible for learning and memory. Such activity may be advantageous in the Alzheimer’s disease.     

Effect of purinergic agonists and antagonists on insulin secretion from INS-1 cells (insulinoma cell line) and rat pancreatic islets

The effects of purinergic agonists on insulin release are controversial in the literature. In our studies (mainly using INS-1 cells, but also using rat pancreatic islets), ATP had a dual effect on insulin release depending on the ATP concentration: increasing insulin release (EC50 approximately/= 0.0032 microM) and inhibiting insulin release (EC50 approximately/= 0.32 microM) at both 5.6 and 8.3 mM glucose. This is compatible with the view that either two different receptors are involved, or the cells desensitize and (or) the effect of an inhibitory degradation product such as adenosine (ectonucleotidase effect) emerges. The same dual effects of ATP on insulin release were obtained using rat pancreatic islets instead of INS-1 cells. ADPbetaS, which is less degradable than ATP and rather specific for P2Y1 receptors, had a dual effect on insulin release at 8.3 mM glucose: stimulatory (EC50 approximately/= 0.02 microM) and inhibitory (EC50 approximately/= 0.32 microM). The effectiveness of this compound indicates the possible involvement of a P2Y1 receptor. 2-Methylthio-ATP exhibited an insulinotropic effect at very high concentrations (EC50 approximately/= 15 microM at 8.3 mM glucose). This indicated that distinct P2X or the P2Y1 receptor may be involved in these insulin-secreting cells. UTP increased insulin release (EC50 approximately/= 2 microM) very weakly, indicating that a P2U receptor (P2X3 or possibly a P2Y2 or P2Y4) are not likely to be involved. Suramin (50 microM) antagonized the insulinotropic effect of ATP (0.01 microM) and UTP (0.32 microM). Since suramin is not selective, the data indicated that various P2X and P2Y receptors may be involved. PPADS (100 microM), a P2X and P2Y1,4,6 receptor antagonist, was ineffective using either low or high concentrations of ATP and ADPbetaS, which combined with the suramin data hints at a P2Y receptor effect of the compounds. Adenosine inhibited insulin release in a concentration-dependent manner. DPCPX (100 microM), an adenosine (A1) receptor antagonist, inhibited the inhibitory effects of both adenosine and of high concentrations of ATP. Adenosine deaminase (1 U/mL) abolished the inhibitory effect of high ATP concentrations, indicating the involvement of the degradation product adenosine. Repetitive addition of ATP did not desensitize the stimulatory effect of ATP. U-73122 (2 microM), a PLC inhibitor, abolished the ATP effect at low concentrations. The data indicate that ATP at low concentrations is effective via P2Y receptors and the PLC-system and not via P2X receptors; it inhibits insulin release at high concentrations by being metabolized to adenosine.     

Nucleotide homeostasis and purinergic nociceptive signaling in rat meninges in migraine-like conditions

Extracellular ATP is suspected to contribute to migraine pain but regulatory mechanisms controlling pro-nociceptive purinergic mechanisms in the meninges remain unknown. We studied the peculiarities of metabolic and signaling pathways of ATP and its downstream metabolites in rat meninges and in cultured trigeminal cells exposed to the migraine mediator calcitonin gene-related peptide (CGRP). Under resting conditions, meningeal ATP and ADP remained at low nanomolar levels, whereas extracellular AMP and adenosine concentrations were one-two orders higher. CGRP increased ATP and ADP levels in meninges and trigeminal cultures and reduced adenosine concentration in trigeminal cells. Degradation rates for exogenous nucleotides remained similar in control and CGRP-treated meninges, indicating that CGRP triggers nucleotide release without affecting nucleotide-inactivating pathways. Lead nitrate-based enzyme histochemistry of whole mount meninges revealed the presence of high ATPase, ADPase, and AMPase activities, primarily localized in the medial meningeal artery. ATP and ADP induced large intracellular Ca²⁺ transients both in neurons and in glial cells whereas AMP and adenosine were ineffective. In trigeminal glia, ATP partially operated via P2X7 receptors. ATP, but not other nucleotides, activated nociceptive spikes in meningeal trigeminal nerve fibers providing a rationale for high degradation rate of pro-nociceptive ATP. Pro-nociceptive effect of ATP in meningeal nerves was reproduced by α,β-meATP operating via P2X3 receptors. Collectively, extracellular ATP, which level is controlled by CGRP, can persistently activate trigeminal nerves in meninges which considered as the origin site of migraine headache. These data are consistent with the purinergic hypothesis of migraine pain and suggest new targets against trigeminal pain.     

The role of nucleotides in the neuron--glia communication responsible for the brain functions

Accumulating findings indicate that nucleotides play an important role in cell-to-cell communication through P2 purinoceptors, even though ATP is recognized primarily to be a source of free energy and nucleotides are key molecules in cells. P2 purinoceptors are divided into two families, ionotropic receptors (P2X) and metabotropic receptors (P2Y). P2X receptors (7 types; P2X(1)-P2X(7)) contain intrinsic pores that open by binding with ATP. P2Y (8 types; P2Y(1, 2, 4, 6, 11, 12, 13,) and (14)) are activated by nucleotides and couple to intracellular second-messenger systems through heteromeric G-proteins. Nucleotides are released or leaked from non-excitable cells as well as neurons in physiological and pathophysiological conditions. One of the most exciting cells in non-excitable cells is the glia cells, which are classified into astrocytes, oligodendrocytes, and microglia. Astrocytes express many types of P2 purinoceptors and release the 'gliotransmitter' ATP to communicate with neurons, microglia and the vascular walls of capillaries. Microglia also express many types of P2 purinoceptors and are known as resident macrophages in the CNS. ATP and other nucleotides work as 'warning molecules' especially through activating microglia in pathophysiological conditions. Microglia play a key role in neuropathic pain and show phagocytosis through nucleotide-evoked activation of P2X(4) and P2Y(6) receptors, respectively. Such strong molecular, cellular and system-level evidence for extracellular nucleotide signaling places nucleotides in the central stage of cell communications in glia/CNS.     

Purinergic mechanisms in the control of gastrointestinal motility

For many years, ATP and adenosine have been implicated in movement regulation of the gastrointestinal tract. They act through three major receptor subtypes: adenosine or P1 receptors, P2X receptors and P2Y receptors. Each of these major receptor types can be subdivided into several different classes and is widely distributed amongst various neurons, muscle types, glia and interstitial cells that regulate intestinal functions. Several key roles for the different receptors and their endogenous ligands have been identified in physiological and pharmacological studies. For example, adenosine acting at A(1) receptors appears to inhibit intestinal motility in various pathological conditions. Similarly, ATP acting at P2Y receptors is an important component of inhibitory neuromuscular transmission, acting as a cotransmitter with nitric oxide. ATP acting at P2X and P2Y(1) receptors is important for synaptic transmission in simple descending excitatory and inhibitory reflex pathways. Some P2Y receptor subtypes prefer uridine nucleotides over purine nucleotides. Thus, roles for UTP and UDP as enteric transmitters in place of ATP cannot be excluded. ATP also appears to be important for sensory transduction, especially in chemosensitive pathways that initiate local inhibitory reflexes. Despite this evidence, data are lacking about the roles of either adenosine or ATP in more complex motility patterns such as segmentation or the interdigestive migrating motor complex. Clarification of roles for purinergic transmission in these common, but understudied, motility patterns will depend on the use of subtype-specific antagonists that in some cases have not yet been developed.     

The role of pannexin 1 in the purinergic regulation of synaptic transmission in mouse motor synapses

The role of pannexin 1 in the release to the extracellular space of ATP/adenosine modulating the acetylcholine (ACh) secretion was studied in mouse diaphragm motor synapses. Using neuromuscular preparations obtained from wild-type and pannexin-1 knockout mice, the miniature endplate potential (MEPPs) and evoked endplate potentials (EPPs) were recorded in combination with pharmacological modulation of P2-type ATP receptors and A₁-type adenosine receptors. Selective inhibition of A₁ receptors with DPCPX or P2 receptors with PPADS increased quantal content of EPPs in wild-type mice. MRS 2211, selective antagonist of P2Y13 receptors, produced the same effect. Activation of receptors A₁ or P2Y₁₃ by their agonists (2-CADO and IDP, respectively) decreased the EPP quantal content. It means that the activity of endogenous ATP and adenosine is synergistic and directed to depression of the ACh release. ARL67156, an inhibitor of synaptic ecto-ATPases, which blocks the hydrolysis of ATP to adenosine and increases the level of ATP in the synaptic cleft, prolonged EPPs without changing their quantal content. In pannexin-1 knockout mice there were no changes in the EPP quantal content and in other parameters of synaptic transmission as compared to wildtype mice. However, downregulation of purinergic effects with antagonists of A₁ or P2 receptors (DPCPX, PPADS, MRS 2211) did not change EPP quantal content and any other parameters of spontaneous or evoked ACh release in all cases. ARL67156 did not alter the temporal parameters of EPPs, either. Nevertheless, 2-CADO, the A₁-type receptor agonist, decreased the EPP quantal content, while the agonist of P2Y₁₃ receptors decreased the MEPP amplitude. Thus, in mice lacking pannexin 1, procedures revealing the presence and regulatory activity of synaptic ATP/adenosine did not change the parameters of synaptic transmission. The obtained data substantiate a mandatory role of pannexin 1 in the purinergic regulation of motor synapse activity by endogenous ATP/adenosine.     

P2X receptors mediated abnormal interaction between satellite glial cells and neurons in visceral pathological changes

The adenosine triphosphate (ATP)‐gated P2X receptor cation channel family consists of permeable ligand‐gated ion channels that expand on the binding of extracellular adenosine 5’‐ATP. ATP‐gated P2X receptors are trimer ion channels that assemble homo or isomer from seven cloned subunits. P2X receptors are discovered mostly in mammalian and are being found in an increasing number of non‐vertebrates, such as zebrafish, bullfrog, and ameba. P2X receptors are involved in many physiological processes, including regulation of heart rhythm and contractility, and regulation of pain, especially chronic pain and glia integration. This review summarizes the current studies on the regulation of P2X receptors in abnormal neuronal‐glial interaction and the pathological changes in viscera, especially in myocardial ischemia.     

Purinoceptors on Neuroglia

Purinergic transmission is one of the most ancient and widespread extracellular signalling systems. In the brain, purinergic signalling plays a unique role in integrating neuronal and glial cellular circuits, as virtually every type of glial cell possesses receptors to purines and pyrimidines. These receptors, represented by metabotropic P1 adenosine receptors, metabotropic P2Y purinoceptors and ionotropic P2X purinoceptors, control numerous physiological functions of glial cells and are intimately involved in virtually every form of neuropathology. In this essay, we provide an in depth overview of purinoceptor distribution in two types of CNS glia—in astrocytes and oligodendrocytes—and discuss their physiological and pathophysiological roles. An erratum to this article can be found at     

Purinergic receptors and gastrointestinal secretomotor function

Secretomotor reflexes in the gastrointestinal (GI) tract are important in the lubrication and movement of digested products, absorption of nutrients, or the diarrhea that occurs in diseases to flush out unwanted microbes. Mechanical or chemical stimulation of mucosal sensory enterochromaffin (EC) cells triggers release of serotonin (5-HT) (among other mediators) and initiates local reflexes by activating intrinsic primary afferent neurons of the submucous plexus. Signals are conveyed to interneurons or secretomotor neurons to stimulate chloride and fluid secretion. Inputs from myenteric neurons modulate secretory rates and reflexes, and special neural circuits exist to coordinate secretion with motility. Cellular components of secretomotor reflexes variably express purinergic receptors for adenosine (A1, A2a, A2b, or A3 receptors) or the nucleotides adenosine 5'-triphosphate (ATP), adenosine diphosphate (ADP), uridine 5'-triphosphate (UTP), or uridine diphosphate (UDP) (P2X(1-7), P2Y(2), P2Y(4), P2Y(6), P2Y(12) receptors). This review focuses on the emerging concepts in our understanding of purinergic regulation at these receptors, and in particular of mechanosensory reflexes. Purinergic inhibitory (A(1), A(3), P2Y(12)) or excitatory (A(2), P2Y(1)) receptors modulate mechanosensitive 5-HT release. Excitatory (P2Y(1), other P2Y, P2X) or inhibitory (A(1), A(3)) receptors are involved in mechanically evoked secretory reflexes or "neurogenic diarrhea." Distinct neural (pre- or postsynaptic) and non-neural distribution profiles of P2X(2), P2X(3), P2X(5), P2Y(1), P2Y(2), P2Y(4), P2Y(6), or P2Y(12) receptors, and for some their effects on neurotransmission, suggests their role in GI secretomotor function. Luminal A(2b), P2Y(2), P2Y(4), and P2Y(6) receptors are involved in fluid and Cl(-), HCO(3) (-), K(+), or mucin secretion. Abnormal receptor expression in GI diseases may be of clinical relevance. Adenosine A(2a) or A(3) receptors are emerging as therapeutic targets in inflammatory bowel diseases (IBD) and gastroprotection; they can also prevent purinergic receptor abnormalities and diarrhea. Purines are emerging as fundamental regulators of enteric secretomotor reflexes in health and disease.     

Purinergic signalling in neuron-glia interactions

Activity-dependent release of ATP from synapses, axons and glia activates purinergic membrane receptors that modulate intracellular calcium and cyclic AMP. This enables glia to detect neural activity and communicate among other glial cells by releasing ATP through membrane channels and vesicles. Through purinergic signalling, impulse activity regulates glial proliferation, motility, survival, differentiation and myelination, and facilitates interactions between neurons, and vascular and immune system cells. Interactions among purinergic, growth factor and cytokine signalling regulate synaptic strength, development and responses to injury. We review the involvement of ATP and adenosine receptors in neuron-glia signalling, including the release and hydrolysis of ATP, how the receptors signal, the pharmacological tools used to study them, and their functional significance.