Introduction: Purinergic transmission

doi:10.1006/smns.1996.0022

Seminars in Neuroscience

Volume 8, Issue 4, August 1996, Pages 171-174

https://doi.org/10.1006/smns.1996.0022 Get rights and content

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An introduction to the roles of purinergic signalling in neurodegeneration, neuroprotection and neuroregeneration
2016, Neuropharmacology
Citation Excerpt :
Ectoenzymes that hydrolyse ATP and adenosine released from cells have been identified (see Zimmermann, 2000; Yegutkin, 2014) and release of purines and pyrimidines from nerves and most non-neuronal cell types in response to mechanical stimulation described (see Burnstock, 1999; Lazarowski et al., 2011). The actions of adenosine in the CNS were recognised early (see Phillis and Wu, 1981; Williams, 1984; Dunwiddie, 1985; Snyder, 1985), while consideration of the role(s) of ATP in the CNS received more attention later (see Bo and Burnstock, 1994; Burnstock, 1996, 2003, 2007b; Gibb and Halliday, 1996; Inoue et al., 1996; Abbracchio, 1997; Illes and Zimmermann, 1999; Masino and Dunwiddie, 2001; North and Verkhratsky, 2006). In particular, fast purinergic synaptic transmission has been clearly identified in the brain (Edwards et al., 1992; Bardoni et al., 1997; Nieber et al., 1997; Pankratov et al., 1999, 2002, 2009; Khakh, 2001; Mori et al., 2001; Robertson et al., 2001).
Purinergic signalling appears to play important roles in neurodegeneration, neuroprotection and neuroregeneration. Initially there is a brief summary of the background of purinergic signalling, including release of purines and pyrimidines from neural and non-neural cells and their ectoenzymatic degradation, and the current characterisation of P1 (adenosine), and P2X (ion channel) and P2Y (G protein-coupled) nucleotide receptor subtypes. There is also coverage of the localization and roles of purinoceptors in the healthy central nervous system. The focus is then on the roles of purinergic signalling in trauma, ischaemia, stroke and in neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's diseases, as well as multiple sclerosis and amyotrophic lateral sclerosis. Neuroprotective mechanisms involving purinergic signalling are considered and its involvement in neuroregeneration, including the role of adult neural stem/progenitor cells.
This article is part of the Special Issue entitled ‘Purines in Neurodegeneration and Neuroregeneration’.
Purinergic signalling: From normal behaviour to pathological brain function
2011, Progress in Neurobiology
Citation Excerpt :
The actions of adenosine in the CNS have been recognised for many years (see Dunwiddie, 1985; Phillis and Wu, 1981; Snyder, 1985; Williams, 1984). However, consideration of the role(s) of ATP in the CNS received less attention until more recently (see Abbracchio, 1997; Bo and Burnstock, 1994; Burnstock, 1996a, 2003, 2007a; Franke and Illes, 2006; Gibb and Halliday, 1996; Illes and Ribeiro, 2004b; Illes and Zimmermann, 1999; Inoue et al., 1996; Krügel et al., 2004a,b; Masino and Dunwiddie, 2001; North and Verkhratsky, 2006; Robertson et al., 2001). In particular, fast purinergic synaptic transmission has been clearly identified in the brain (Khakh, 2001; Pankratov et al., 2009).
Purinergic neurotransmission, involving release of ATP as an efferent neurotransmitter was first proposed in 1972. Later, ATP was recognised as a cotransmitter in peripheral nerves and more recently as a cotransmitter with glutamate, noradrenaline, GABA, acetylcholine and dopamine in the CNS. Both ATP, together with some of its enzymatic breakdown products (ADP and adenosine) and uracil nucleotides are now recognised to act via P2X ion channels and P1 and P2Y G protein-coupled receptors, which are widely expressed in the brain. They mediate both fast signalling in neurotransmission and neuromodulation and long-term (trophic) signalling in cell proliferation, differentiation and death. Purinergic signalling is prominent in neurone–glial cell interactions. In this review we discuss first the evidence implicating purinergic signalling in normal behaviour, including learning and memory, sleep and arousal, locomotor activity and exploration, feeding behaviour and mood and motivation. Then we turn to the involvement of P1 and P2 receptors in pathological brain function; firstly in trauma, ischemia and stroke, then in neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's, as well as multiple sclerosis and amyotrophic lateral sclerosis. Finally, the role of purinergic signalling in neuropsychiatric diseases (including schizophrenia), epilepsy, migraine, cognitive impairment and neuropathic pain will be considered.
Historical review: ATP as a neurotransmitter
2006, Trends in Pharmacological Sciences
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.
Changes in expression of P2X purinoceptors in rat cerebellum during postnatal development
2005, Developmental Brain Research
Changes in expression of P2X receptors (P2X_1–7) during postnatal development of the rat cerebellum are described. At P3, immunoreactivity (ir) to all the P2X receptors, except for P2X₃ receptors, was found in Purkinje cells and deep cerebellar nuclei, P2X₅-ir being most prominent. Granular and microglial cells were labeled for P2X₅ (weakly) and P2X₄ receptors, respectively. At P7, expression of all the P2X receptors (with the exception of P2X₃) was up-regulated, P2X₅ and P2X₆ receptors being most prominent. Scattered P2X receptor-ir in unipolar brush cells in the granular cell layer and P2X₁- and P2X₇-ir of microglial cells was also present. At P14, the dendritic trees of Purkinje cells were intensely labeled by P2X_1–7 receptor antibodies, except for P2X₃, while P2X₁, P2X₄ and P2X₇ receptor immunostaining in microglial cells and P2X₅ receptor immunostaining in granular cells was up-regulated. At P21, expression of all P2X receptors (except P2X₃) was down-regulated in the Purkinje cells and deep cerebellar nuclei; P2X₁, P2X₄ and P2X₇ receptors-ir was present in microglial cells. In contrast, expression of P2X₅-ir in granular cells was up-regulated. At P60, expression levels of all the P2X receptors (except P2X₃) were similar with those at P21. In double-labeling experiments, almost all the P2X-ir Purkinje cells were immunoreactive for calbindin-D28k, while 60–80% of P2X-ir cells in the granular cell layer were immunoreactive for calretinin. The possible short- and long-term functional significance of the changes in expression of P2X receptors during postnatal development is discussed.
Purinergic Neurotransmission
2004, Primer on the Autonomic Nervous System: Second Edition
An increase in the role of adenosine triphosphate (ATP) as a cotransmitter has been demonstrated in pathologic conditions, including interstitial cystitis and hypertension. In addition to rapid signaling during neurotransmission, ATP appears to act as a long-term (trophic) signaling molecule during development and regeneration, sometimes synergistically with growth factors. Purinergic mechanosensory transduction has been proposed where ATP released from epithelial cells closely associated with sensory nerve terminals labeled with P2X₃ receptors leads to the activation of sensory nerve activity related to physiologic events—such as bladder voiding—or to nociception or both. Following the proposal by Burnstock in 1976 that nerves might store and release more than one transmitter, there is now considerable experimental support for ATP as a cotransmitter with classical transmitters and neuropeptides in most major nerve types. ATP released from nerves may also act as a prejunctional modulator of cotransmitter release (often through adenosine) or as a postjunctional modulator of cotransmitter actions.
Purinergic Receptors in the Nervous System
2003, Current Topics in Membranes
Citation Excerpt :
The actions of adenosine in the CNS have been recognized for many years beginning with the work of Feldberg and Sherwood (1954), which included ataxia and a tendency to sleep following intracerebroventricular injections (see reviews by Reddington et al., 1983; Williams, 1984; Snyder, 1985; Dunwiddie, 1985; Marangos and Boulenger, 1985; Phillis et al., 1986; Ribeiro, 1995; Fredholm, 1995). However, consideration of the role(s) of ATP in the CNS received less attention until recently (see Burnstock, 1996, 1977; Phillis and Wu, 1981; Inoue et al., 1996; Dunwiddie et al., 1996; Gibb and Halliday, 1996; Abbracchio, 1997; Robertson, 1998; Illes and Zimmermann, 1999; Nörenberg and Illes, 2000). In particular, purinergic synaptic transmission has been clearly identified in the brain (Khakh, 2001).
This chapter focuses on the localization and roles of purinergic receptor subtypes in the central nervous system (CNS), as comprehensive reviews of purinergic signaling in the peripheral nervous system. The concept of purinergic neurotransmission is the existence of postjunctional purinergic receptors. A basis for distinguishing two types of purinoceptor, identiﬁed as P1 and P2 [for adenosine and adenosine triphosphate (ATP)/adenosine diphosphate (ADP), respectively], was proposed by Burnstock in 1978, but it was not until 1985 that a basis for distinguishing two types of P2 receptor(P2X and P2Y) was suggested, largely on the basis of pharmacological criteria. Pamela Holton provided the ﬁrst hint of a transmitter role for adenosine triphosphate (ATP) in the nervous system by demonstrating the release of ATP during antidromic stimulation of sensory nerves . Then, in 1970, it was proposed that nonadrenergic, noncholinergic (NANC) nerves supplying smooth muscle of the gut and bladder utilized ATP as a neurotransmitter. The experimental evidence included the mimicry of the NANC nerve-mediated response by ATP; the measurement of the release of ATP during the stimulation of NANC nerves with luciferin-luciferase luminometry; histochemical labeling of the subpopulations of neurons in the gut and the bladder with quinacrine—a ﬂuorescent dye known to selectively label high levels of ATP bound to peptides; and the demonstration that the slowly degradable analogue of ATP—αβ-methylene ATP, which produces selective desensitization of the ATP receptor—blocks the responses to NANC nerve stimulation.

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Introduction: Purinergic transmission