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J Physiol 586.14 (2008) pp 3307–3312 3307

TOP ICAL REVIEW

Unresolved issues and controversies in purinergicsignalling

Geoffrey Burnstock

Autonomic Neuroscience Centre, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, UK

Some areas of current interest in the rapidly expanding purinergic signalling field that arecontroversial or are unresolved are highlighted in this review. These include the mechanismsunderlying: ATP transport across cell and vesicle membranes; the interaction of multiplereceptors for purines and pyrimidines on single cells; the blocking effect of antagonists to P2X4

and P2X7 receptors expressed by microglial cells in neuropathic and inflammatory pain; andthe complex actions mediated by P2X7 receptors. Some desirable areas for further research arealso discussed including: comparative studies of the evolution of purinergic signalling; studiesof purinergic signalling in development and regeneration, including the involvement of stemcells; behavioural studies; and therapeutic strategies.

(Received 25 April 2008; accepted after revision 19 May 2008; first published online 22 May 2008)Corresponding author G. Burnstock: Autonomic Neuroscience Centre, Royal Free and University College MedicalSchool, Rowland Hill Street, London NW3 2PF, UK. Email: [email protected]

The concept of purinergic signalling (i.e. ATP as anextracellular signalling molecule and neurotransmitter)was introduced in a Pharmacological Reviews article in1972 (Burnstock, 1972). Perhaps because of the emphasison ATP as an intracellular energy source, it was regardedby many as unlikely that such a ubiquitous molecule wouldbe an extracellular messenger. However, after receptorsubtypes for ATP and its breakdown product, adenosine,were cloned and characterized in the early 1990s andpurinergic synaptic, as well as neuromuscular, trans-mission was established, the concept is now wellestablished and indeed the field is expanding rapidly (seeBurnstock, 2007a). Nevertheless, we are still on the steepslope of the discovery curve and there are plenty of gaps inour knowledge, a number of controversial areas still to beresolved and exciting new areas to explore, some of whichwill be addressed in this short review.

Mechanism(s) of ATP transport

For many years it was thought that, apart from nerves, theonly source of extracellular ATP acting on purinoceptorswas damaged or dying cells. However, it is now recognizedthat ATP release from healthy cells is a physiologicalmechanism. ATP is released from many non-neuronalcell types during mechanical deformation in responseto shear stress, stretch, or osmotic swelling, as well ashypoxia and stimulation by various agents. There is anactive debate about the precise transport mechanism(s)involved in ATP release. There is compelling evidence

for exocytotic vesicular release of ATP from nerves,but for ATP release from non-neuronal cells varioustransport mechanisms have been proposed, includingATP-binding cassette (ABC) transporters, connexin orpannexin hemichannels, and possibly plasmalemmalvoltage-dependent anion or P2X7 receptor channels, aswell as vesicular release. Perhaps surprisingly, evidencewas presented that the release of ATP from vascular endo-thelial cells (Bodin & Burnstock, 2001) and from urothelialcells in the ureter (Knight et al. 2002) is largelyvesicular, since monensin and brefeldin A, which interferewith vesicular formation and trafficking, inhibiteddistension-evoked ATP release, but not gadolinium, aninhibitor of stretch-activated channels, or glibenclamide,an inhibitor of members of the ABC protein family.Since then, exocytotic vesicular release of ATP fromosteoblasts, fibroblasts and astrocytes has also beenreported. There is increased release of ATP from endo-thelial cells during acute inflammation. Local probes forreal-time measurement of ATP release in biological tissueshave been developed recently (see Corriden et al. 2007).

Another question that has been raised over the yearsconcerns the mechanism of transport of ATP into synapticvesicles, but this might have been resolved recently withthe identification of a vesicular nucleotide transporter(Sawada et al. 2008).

Multiple receptors and single cells

On the basis of cloning, studies of transductionmechanisms and pharmacology, receptor subtypes for

C© 2008 The Author. Journal compilation C© 2008 The Physiological Society DOI: 10.1113/jphysiol.2008.155903

3308 G. Burnstock J Physiol 586.14

Figure 1A, the molecular topology of the P2X1–6 and the P2X7 receptors. The key feature of the P2X7 receptordistinguishing it from the other P2X receptors is its long carboxy-terminus tail. B, the 3 different forms of the P2X7

receptor upon activation by ATP: closed channel, open channel, and pore formation. Brief ATP activation leads toopening of an ion channel permeable to small ions, such as Na+, K+ and Ca2+, whereas prolonged ATP exposureresults in the pore formation, permeable to high molecular weight organic cations, e.g. N-methyl-D-glucamine(NMDG) and YO-PRO-1 dye. C, naturally occurring splice variants of the human P2X7 gene are shown. Exons are

C© 2008 The Author. Journal compilation C© 2008 The Physiological Society

J Physiol 586.14 Unresolved issues and controversies in purinergic signalling 3309

purines and pyrimidines have been identified: P1adenosine receptors (A1, A2A, A2B and A3 subtypes),P2X ionotropic receptors (P2X1–7 subtypes formingboth homomultimers and heteromultimers) and P2Ymetabotropic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11,P2Y12, P2Y13 and P2Y14), some of which are also sensitiveto pyrimidines (Ralevic & Burnstock, 1998; Burnstock,2007b). Many non-neuronal cells, as well as neurones,express multiple receptor subtypes (see Burnstock &Knight, 2004) and we face questions about how theyinteract in controlling cellular activity (see Volonte et al.2006). Some receptors mediate fast signalling, such assecretion, neurotransmission or neuromodulation, whileothers mediate longer-term ‘trophic’ signalling, regulatingcell proliferation, differentiation, motility and death.Some receptors appear to operate only in pathologicalconditions. Perhaps the best known example of cellswith multiple receptors with different functional rolesis microglia. P2Y12 and P2X4 receptors mediate chemo-taxis and migration to sites of injury, while P2X1 and/orP2X2 receptors may mediate the change of phenotypefrom ‘resting’ microglia with elaborate processes to the‘activated’ amoeboid form at the sites of injury. P2Y6

receptors are strongly expressed in activated microglia,where they mediate phagocytotic activity (Koizumi et al.2007). P2X4 and P2X7 receptors mediate neuropathic painand P1 (adenosine) receptors mediate neuroprotection,although the underlying mechanisms are not yet under-stood.

Neuropathic and inflammatory pain

This is an exciting area of strong current interest. P2X3

receptors were cloned in 1995 (Chen et al. 1995; Lewiset al. 1995) and shown to be localized in the periphery onnociceptive sensory fibres arising from sensory ganglia,and on the central terminals in inner lamina 2 of thedorsal horn of the spinal cord (Bradbury et al. 1998).P2X3 receptors and P2X2/3 heteromultimer receptorswere shown to mediate purinergic mechanosensorytransduction that initiates pain in visceral organs,including bladder, ureter and gut (Burnstock, 2001a).

P2X3 receptors in the central nervous system (CNS)have also been shown to be involved in neuropathic and

numbered and indicated by boxes. The newly identified exon N3 is indicated. Introns are represented by horizontallines between the exons. Below the genomic structure is depicted the P2X7 transcript with relevant domainsindicated. D, the exon arrangement of the various splice variants isolated is shown. New stop codons are indicatedby asterisks and new start codons indicated by the letter M. The approximate positions of PCR primers used forreal-time expression analysis are indicated by arrowheads placed below variants A, B and H. The sequences of theseven splice variants have been deposited in GenBank with the following accession nos.: AY847298, AY847299,AY847300, AY847301, AY847302, AY847303 and AY847304. (A and B are reproduced from Gunosewoyo et al.2007, with permission from Bentham Science Publishers, Ltd; C and D are reproduced from Cheewatrakoolponget al. 2005, with permission from Elsevier.)

inflammatory pain (see Jarvis, 2003). Selective antagoniststo P2X3 and P2X2/3 receptors prevent allodynia producedby intrathecal administration of ATP in rats (Nakagawaet al. 2007). P2X3 and P2X2/3 receptor-dependent cytosolicphospholipase A2 activity in primary sensory neurons isclaimed to be a key event in neuropathic pain (Tsudaet al. 2007; Wirkner et al. 2007). The cyclic AMP sensorEpac appears to play a critical role in P2X3 sensitizationin inflammation. Short interfering RNA (siRNA) for theP2X3 receptor relieves chronic neuropathic pain (Dornet al. 2004). P2X3 receptors mediate heat hyperalgesia in arat model of trigeminal neuropathic pain (Shinoda et al.2007).

Perhaps surprisingly, in a seminal paper, Tsuda et al.(2003) showed that, after nerve injury, up-regulatedexpression of P2X4 receptors on spinal microglia mediateallodynia and supporting evidence has followed (see Tranget al. 2006; Zhang et al. 2008). Further, a number ofpapers have shown that antagonists to P2X7 receptorsexpressed on microglia also significantly reduce neuro-pathic pain (Donnelly-Roberts & Jarvis, 2007; Fulgenziet al. 2008), which has also been shown to be abolishedin P2X7 knockout mice (Chessell et al. 2005). P2Y12

receptor up-regulation in activated microglia has also beenclaimed recently as a gateway of p38 signalling in neuro-pathic pain (Kobayashi et al. 2008). However, unresolvedissues concern the mechanism underlying these strikingeffects and the interactions of the different P2 receptorsubtypes involved in neuropathic and inflammatory pain(see Khakh & North, 2006).

P2X7 receptors

One of the most controversial areas concerns themultiple identity and modes of action of P2X7 receptors(North, 2002; Sperlagh et al. 2006; Anderson &Nedergaard, 2006; Khakh & North, 2006). Of theP2X receptor family, it is unusual in that it hasan extremely long C-terminal sequence (240 aminoacids) (Fig. 1A). In addition to the opening of theusual cation channel with low concentrations of ATP,when occupied by high concentrations of ATP (or2′-3′-O-(4-benzoylbenzoyl)-ATP), large pores permeableto molecules up to 900 Da are opened (Fig. 1B), which



lead to apoptosis and cell death in most situations,although proliferative actions via P2X7 receptors havealso been described. Occupation of P2X7 receptorsleads to blebbing (the function of which is still notclear) and shedding of microvesicles associated withthe production of pro-inflammatory cytokines, includinginterleukin-1β (IL-1β) and transforming growth factor β

mRNA expression. The P2X7 receptor field is furthercomplicated by the identification of a number of poly-morphisms or spliced variants (Cheewatrakoolpong et al.2005; Shemon et al. 2006; Fonfria et al. 2008) (Fig. 1C andD) and by a complex story regarding antagonists, someof which work in rats but not in humans and vice versa(Gever et al. 2006; Gunosewoyo et al. 2007).

Other questions need to be resolved. For example,is pannexin 1 part of the pore-forming unit of theP2X7 receptor death complex and release of IL-1β

(Locovei et al. 2007; Pelegrin & Surprenant, 2007)? Ismitogen-activated protein kinase (MAPK) involved inP2X7 receptor-mediated changes in cellular permeability?Is Cl− influx involved in P2X7 receptor-mediatedapoptotic cell death? Do P2X7 receptors play a pivotal rolein immuno-inflammatory responses (Chen & Brosnan,2006)? What is the significance of P2X7 receptor expressionon the nuclear membrane (Atkinson et al. 2002)? Isglutamate release from astrocytes mediated by P2X7

receptors? Is the P2X7 receptor located on presynapticand/or postsynaptic membranes in the brain or largelyexpressed on glial cells? There is still much to be resolved,but it is important because of potential therapeuticdevelopments related to the P2X7 receptor in cancer,inflammatory pain and kidney disease (see Burnstock,2006).

Evolution of purinergic signalling

There are many studies of the effect of nucleotides andnucleosides in most invertebrate phyla as well as inlower vertebrates, suggesting that P1 (adenosine), P2Xand P2Y receptors were all present early in evolution(see Burnstock, 1996). More recently receptors havebeen cloned in both Dictyostelium discoideum (a socialamoeba) and Schistosoma mansoni (a parasitic trematode)that resemble P2X receptors in mammals (Agboh et al.2004; Fountain et al. 2007). Also there have been recentpapers suggesting that purinergic signalling is involvedin regeneration of plants (Demidchik & Maathuis, 2007;Roux & Steinebrunner, 2007). It is important that moremolecular studies are carried out to identify purinoceptorsin invertebrates, to establish the primitive nature of thepurinergic signalling system and to give insights intothe advantages of this system leading to its retention inmammals.

Development and regeneration

The importance of purinergic signalling in embryologicaland postnatal development is emerging (see Burnstock,2001b; Zimmermann, 2006), where transient expression ofpurinoceptor subtypes suggests that they may be involvedin proliferation, differentiation and cell death of specificsequential cellular steps in the developmental process.However, hopefully this is only the beginning of studiesin this interesting area with the need for further work,particularly those relating purinergic messengers to theinfluence of growth factors and genetic programming.

There are also an increasing number of studies of the roleof purines and pyrimidines in regeneration and woundhealing (see Abbracchio & Burnstock, 1998; Burnstock,2007a) and studies of the involvement of purinergicsignalling in stem cell activities are just beginning (e.g.Mishra et al. 2006; Heo & Han, 2006; Coppi et al. 2007),but more are needed.

Behavioural studies

At one physiological level, it is now clear that purinergicsynaptic neurotransmission and neuromodulation iswidespread in the CNS and that there is complexexpression of different purinoceptor subtypes on bothneurons and glial cells in different regions of the brain(see Burnstock, 2007a). However, there are relativelyfew studies of the behavioural roles of purines andpyrimidines. There are some reports of their roles inlearning and memory, feeding and locomotive behaviourand some hints about their involvement in neuro-degenerative diseases and psychiatric disorders, but muchmore research is needed in this area. Perhaps the mainlimiting factor for such studies is the absence at presentof selective and stable purinoceptor subtype agonists andantagonists that can cross the blood–brain barrier.

Therapeutic developments

There has been considerable enthusiastic exploration inrecent years for the use of purinergic agents for thetreatment of a number of diseases, including: stroke,thrombosis, bladder incontinence, pain, cystic fibrosis,dry eye, cancer, diabetes and osteoporosis (see Burnstock,2006). Clopidogrel, a breakdown product of which blocksP2Y12 receptor-mediated platelet aggregation, is nowwidely used for the treatment of stroke and thrombosis.However, for other diseases, we still await the synthesisby medicinal chemists of small molecule drugs that arestable in vivo and are orally bioavailable. For example,Roche Bioscience (Palo Alto) have recently produced aP2X3 receptor antagonist (RO3) that seems to satisfythese criteria and is in clinical trial for pain and bladderincontinence (Gever et al. 2006).


J Physiol 586.14 Unresolved issues and controversies in purinergic signalling 3311

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