Trends in Pharmacological Sciences
Historical review: ATP as a neurotransmitter
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
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