Historical review: ATP as a neurotransmitter

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Purinergic signalling is now recognized to be involved in a wide range of activities of the nervous system, including neuroprotection, central control of autonomic functions, neural–glial interactions, control of vessel tone and angiogenesis, pain and mechanosensory transduction and the physiology of the special senses. In this article, I give a personal retrospective of the discovery of purinergic neurotransmission in the early 1970s, the struggle for its acceptance for ∼20 years, the expansion into purinergic cotransmission and its eventual acceptance when receptor subtypes for ATP were cloned and characterized and when purinergic synaptic transmission between neurons in the brain and peripheral ganglia was described in the early 1990s. I also discuss the current status of the field, including recent interest in the pathophysiology of purinergic signalling and its therapeutic potential.

Section snippets

Early history

The diverse range of physiological actions of ATP was recognized relatively early. For example, in 1929, Drury and Szent-Györgyi [1] demonstrated the potent extracellular actions of ATP and adenosine on the heart and coronary blood vessels. The published follow-up studies of the cardiovascular actions of purines during the next 20 years were reviewed by Green and Stoner in 1950 in a book entitled ‘Biological Actions of the Adenine Nucleotides’ [2]. In 1948, Emmelin and Feldberg [3] demonstrated

‘Non-adrenergic, non-cholinergic neurotransmission’

After completing studies of noradrenaline (NA)- and ACh-mediated responses of the guinea-pig taenia coli in Edith Bülbring's laboratory at the Department of Pharmacology, Oxford [12], I moved to Melbourne, Australia. There, I set up the sucrose gap apparatus in my laboratory for recording continuous correlated changes in electrical and mechanical activity of smooth muscle [13]. Graeme Campbell and Max Bennett were working with me, and one day in 1962 we decided to look at the direct response of

The ‘purinergic’ hypothesis

Several years later, after many experiments, we published a study that suggested that the NANC transmitter in the guinea-pig taenia coli and stomach, rabbit ileum, frog stomach and turkey gizzard was ATP [18]. The experimental evidence included: mimicry of the NANC nerve-mediated response by ATP; measurement of the release of ATP during stimulation of NANC nerves with luciferin–luciferase luminometry; histochemical labelling of subpopulations of neurons in the gut with quinacrine, a fluorescent

Purinergic cotransmission

Another concept that has had a significant influence on our understanding of purinergic transmission is cotransmission. I wrote a Commentary in Neuroscience in 1976 entitled: ‘Do some nerves release more than one transmitter?’ [25]; this challenged the single neurotransmitter concept, which became known as ‘Dale's Principle’, even though Dale himself never defined it as such. The commentary was based on hints about cotransmission in the early literature describing both vertebrate and

Purine receptors

Implicit in the purinergic neurotransmission hypothesis was the presence of purinoceptors. A basis for distinguishing two types of purinoceptor, identified as P1 and P2 for adenosine, and ATP and ADP, respectively, was recognized [39]. This helped resolve some of the ambiguities in earlier reports, which were complicated by the breakdown of ATP to adenosine by ectoenzymes, so that some of the actions of ATP were directly on P2 receptors, whereas others were due to the indirect action of

ATP release and degradation

There is clear evidence for exocytotic vesicular release of ATP from nerves, and the concentration of nucleotides in vesicles are claimed to be up to 1000 mM. It was generally assumed that the main source of ATP acting on purinoceptors was damaged or dying cells. However, it is now recognized that ATP release from many cells is a physiological or pathophysiological response to mechanical stress, hypoxia, inflammation and some agonists [53]. There is debate, however, about the ATP transport

Physiology and pathophysiology of neurotransmission

The purinergic neurotransmission field is expanding rapidly; there is increasing interest in the physiology and pathophysiology of this neurosignalling system and therapeutic interventions are being explored. The first clear evidence for nerve–nerve purinergic synaptic transmission was published in 1992 55, 56, 57. Synaptic potentials in the coeliac ganglion and in the medial habenula in the brain were reversibly antagonised by the anti-trypanosomal agent suramin. Since then, many articles have

Neuroprotection

In the brain, purinergic signalling is involved in nervous tissue remodelling following trauma, stroke, ischaemia or neurodegenerative disorders [58]. The hippocampus of chronic epileptic rats shows abnormal responses to ATP that are associated with increased expression of P2X7 receptors. Neuronal injury releases fibroblast growth factor, epidermal growth factor and platelet-derived growth factor. In combination with these growth factors, ATP can stimulate astrocyte proliferation, contributing

CNS control of autonomic function

Functional interactions seem likely to occur between purinergic and nitrergic neurotransmitter systems; these interactions might be important for the regulation of hormone secretion and body temperature at the hypothalamic level and for cardiovascular and respiratory control at the level of the brainstem 60, 61. The nucleus tractus solitarius (NTS) is a major integrative centre of the brain stem involved in reflex control of the cardiovascular system, and stimulation of P2X receptors in the NTS

Neuron–glia interactions

ATP is an extracellular signalling molecule between neurons and glial cells. ATP released from astrocytes might be important in triggering cellular responses to trauma and ischaemia by initiating and maintaining reactive astrogliosis, which involves striking changes in the proliferation and morphology of astrocytes and microglia. Some of the responses to ATP released during brain injury are neuroprotective, but at higher concentrations ATP contributes to the pathophysiology initiated after

Purine transmitter and receptor plasticity

The autonomic nervous system shows marked plasticity: that is, the expression of cotransmitters and receptors show dramatic changes during development and aging, in nerves that remain after trauma or surgery and in disease conditions. There are several examples where the purinergic component of cotransmission is increased in pathological conditions [51]. The parasympathetic purinergic nerve-mediated component of contraction of the human bladder is increased to 40% in pathophysiological

Dual purinergic neural and endothelial control of vascular tone and angiogenesis

ATP and adenosine are involved in the mechanisms that underlie local control of vessel tone in addition to cell migration, proliferation and death during angiogenesis, atherosclerosis and restenosis following angioplasty [68]. ATP, released as a cotransmitter from sympathetic nerves, constricts vascular smooth muscle via P2X receptors, whereas ATP released from sensory-motor nerves during ‘axon reflex’ activity dilates vessels via P2Y receptors. Furthermore, ATP released from endothelial cells

Pain and purinergic mechanosensory transduction

The involvement of ATP in the initiation of pain was recognized first in 1966 and later in 1977 using human skin blisters 69, 70. A major advance was made when the P2X3 ionotropic receptor was cloned in 1995 and shown later to be localized predominantly in the subpopulation of small nociceptive sensory nerves that label with isolectin IB4 in dorsal root ganglia (DRG), whose central projections terminate in inner lamina II of the dorsal horn [71]. In 1996, I proposed a unifying ‘purinergic’

Eye

P2X2 and P2X3 receptor mRNA is present in the retina and receptor protein expressed in retinal ganglion cells [86]. P2X3 receptors are also present on Müller cells, which release ATP during Ca2+ wave propagation. ATP, acting via both P2X and P2Y receptors, modulates retinal neurotransmission, affecting retinal blood flow and intraocular pressure. Topical application of diadenosine tetraphosphate has been proposed for the lowering of intraocular pressure in glaucoma [87]. The formation of P2X7

Concluding remarks

The purinergic transmission hypothesis underwent strong resistance after it was first proposed in 1972, but following the cloning and characterization of purinoceptor subtypes and the recognition of purinergic synaptic transmission in the brain and autonomic ganglia in the early 1990s it gained wide recognition. There is now much interest in the physiology and pathophysiology of purinergic cotransmission and purinergic interactions between neurons and glial cells in both the CNS and the

References (100)

  • M.P. Abbracchio et al.

    Purinoceptors: are there families of P2X and P2Y purinoceptors?

    Pharmacol. Therap.

    (1994)
  • T.E. Webb

    Cloning and functional expression of a brain G-protein-coupled ATP receptor

    FEBS Lett.

    (1993)
  • G. Burnstock et al.

    Cellular distribution and functions of P2 receptor subtypes in different systems

    Int. Rev. Cytol.

    (2004)
  • G. Burnstock

    Purinergic receptors in the nervous system

  • P.M. Dunn

    P2X receptors in peripheral neurones

    Prog. Neurobiol.

    (2001)
  • G. James et al.

    P2Y and P2X purinoceptor mediated Ca2+ signalling in glial cell pathology in the central nervous system

    Eur. J. Pharmacol.

    (2002)
  • L.K. Parvathenani

    P2X7 mediates superoxide production in primary microglia and is up-regulated in a transgenic mouse model of Alzheimer's disease

    J. Biol. Chem.

    (2003)
  • O. Vonend

    Glomerular expression of the ATP-sensitive P2X7 receptor in diabetic and hypertensive rat models

    Kidney Int.

    (2004)
  • T. Bleehen et al.

    Observations on the algogenic actions of adenosine compounds on human blister base preparation

    Pain

    (1977)
  • E.J. Bradbury

    The expression of P2X3 purinoreceptors in sensory neurons: effects of axotomy and glial-derived neurotrophic factor

    Mol. Cell. Neurosci.

    (1998)
  • G. Burnstock

    A unifying purinergic hypothesis for the initiation of pain

    Lancet

    (1996)
  • G. Burnstock

    Purine-mediated signalling in pain and visceral perception

    Trends Pharmacol. Sci.

    (2001)
  • W. Rong et al.

    Activation of ureter nociceptors by exogenous and endogenous ATP in guinea pig

    Neuropharmacology

    (2004)
  • G. Wynn

    Purinergic mechanisms contribute to mechanosensory transduction in the rat colorectum

    Gastroenterology

    (2003)
  • L.S. Stone et al.

    The pain of antisense: in vivo application of antisense oligonucleotides for functional genomics in pain and analgesia

    Adv. Drug Deliv. Rev.

    (2003)
  • S.D. Liang

    Effect of tetramethylpyrazine on acute nociception mediated by signaling of P2X receptor activation in rat

    Brain Res.

    (2004)
  • T.H. Wheeler-Schilling

    Identification of purinergic receptors in retinal ganglion cells

    Brain Res. Mol. Brain Res.

    (2001)
  • J.E. Gale

    A mechanism for sensing noise damage in the inner ear

    Curr. Biol.

    (2004)
  • G. Burnstock

    Introduction: ATP and its metabolites as potent extracellular agonists

  • A.N. Drury et al.

    The physiological activity of adenine compounds with special reference to their action upon the mammalian heart

    J. Physiol.

    (1929)
  • Green, H.N. and Stoner, H.B., eds (1950) Biological Actions of the Adenine Nucleotides, H.K. Lewis and Co.,...
  • N. Emmelin et al.

    Systemic effects of adenosine triphosphate

    Br. J. Pharmacol. Chemother.

    (1948)
  • A. Galindo

    Micro-iontophoretic studies on neurones in the cuneate nucleus

    J. Physiol.

    (1967)
  • P. Holton

    The liberation of adenosine triphosphate on antidromic stimulation of sensory nerves

    J. Physiol.

    (1959)
  • F. Buchthal et al.

    Interaction between acetylcholine and adenosine triphosphate in normal, curarised and denervated muscle

    Acta Physiol. Scand.

    (1948)
  • B.L. Ginsborg et al.

    The effect of adenosine on the release of the transmitter from the phrenic nerve of the rat

    J. Physiol.

    (1972)
  • K. Boettge

    Das adenylsäuresystem. Neuere ergebnisse und probleme

    Arzneimittelforschung

    (1957)
  • R.M. Berne

    Cardiac nucleotides in hypoxia: possible role in regulation of coronary blood flow

    Am. J. Physiol.

    (1963)
  • G. Burnstock

    Hypoxia, endothelium and purines

    Drug Dev. Res.

    (1993)
  • G. Burnstock

    History of extracellular nucleotides and their receptors

  • G. Burnstock

    The action of adrenaline on excitability and membrane potential in the taenia coli of the guinea-pig and the effect of DNP on this action and on the action of acetylcholine

    J. Physiol.

    (1958)
  • G. Burnstock et al.

    A method for studying the effects of ions and drugs on the resting and action potentials in smooth muscle with external electrodes

    J. Physiol.

    (1958)
  • G. Burnstock

    Inhibition of the smooth muscle of the taenia coli

    Nature

    (1963)
  • J. Martinson et al.

    Excitatory and inhibitory effects of vagus stimulation on gastric motility in the cat

    Acta Physiol. Scand.

    (1963)
  • G. Burnstock

    The inhibitory innervation of the taenia of the guinea-pig caecum

    J. Physiol.

    (1966)
  • G. Burnstock

    Evidence that adenosine triphosphate or a related nucleotide is the transmitter substance released by non-adrenergic inhibitory nerves in the gut

    Br. J. Pharmacol.

    (1970)
  • G. Burnstock

    Atropine resistant excitation of the urinary bladder: the possibility of transmission via nerves releasing a purine nucleotide

    Br. J. Pharmacol.

    (1972)
  • G. Burnstock

    Purinergic nerves

    Pharmacol. Rev.

    (1972)
  • G. Burnstock

    Purinoceptors: ontogeny and phylogeny

    Drug Dev. Res.

    (1996)
  • Abbracchio, M.P. and Williams, M. (eds) (2001) Handbook of Experimental Pharmacology: Purinergic and Pyrimidinergic...
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