Chapter 2 Modulation of purinergic neurotransmission

doi:10.1016/S0079-6123(08)63542-6

Progress in Brain Research

Volume 120, 1999, Pages 11-20

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This chapter highlights some recent developments in the understanding of ATP as a cotransmitter. Four main topics of purinergic research are emphasized in the chapter: the storage and release of ATP and its regulation, the structure and classification of P2-receptor subtypes, the postjunctional effector mechanisms by which ATP mediates its neurotransmitter actions, and the mechanism of inactivation of the neurotransmitter actions of ATP by ATPases. Recent studies indicate that there are more than one population of storage vesicles in the nerves, as the release of various cotransmitters varies over time and can be differentially modulated by drugs. The subclassification of P2 receptors has advanced in the past few years because of the use of molecular biology methods allowing the cloning and expression of 14 different subclasses of P2 receptors, seven P2X, and seven P2Y. Determination of the functional significance of various receptor subtypes would be helped by the development of selective agonists and antagonists.

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Cited by (39)

ATP as a cotransmitter in sympathetic and parasympathetic nerves - another Burnstock legacy
2021, Autonomic Neuroscience: Basic and Clinical
Citation Excerpt :
Together, these processes raise cytoplasmic [Ca2+] high enough to induce contraction. In the vas deferens of a variety of species, including humans (Banks et al., 2006), combined pharmacological inhibition of P2X1R and α1-adrenoceptors has demonstrated that the initial phasic component of neurogenic contractions is largely purinergic, whereas the secondary, tonic phase is mostly noradrenergic (see Sneddon et al., 1996, 1999). The vas deferens of P2X1R-knockout mice displayed much smaller neurogenic contractions than wild-type animals and this was associated with a 90% decrease in fertility (Mulryan et al., 2000).
Geoff Burnstock created an outstanding scientific legacy that includes identification of adenosine 5′-triphosphate (ATP) as an inhibitory neurotransmitter in the gut, the discovery and characterisation of a large family of purine and uridine nucleotide-sensitive ionotropic P2X and metabotropic P2Y receptors and the demonstration that ATP is as an excitatory cotransmitter in autonomic nerves. The evidence for cotransmission includes that: 1) ATP is costored with noradrenaline in synaptic vesicles in postganglionic sympathetic nerves innervating smooth muscle tissues, including the vas deferens and most arteries. 2) When coreleased with noradrenaline, ATP acts at postjunctional P2X1 receptors to elicit depolarisation, Ca²⁺ influx, Ca²⁺ sensitisation and contraction. 3) ATP is also coreleased with acetylcholine from postganglionic parasympathetic nerves innervating the urinary bladder, where it stimulates postjunctional P2X1 receptors, and a second, as yet unidentified site to evoke contraction of detrusor smooth muscle. In both systems membrane-bound ecto-enzymes and soluble nucleotidases released from postganglionic nerves dephosphorylate ATP and so terminate its neurotransmitter actions. Currently, the most promising potential area of therapeutic application relating to cotransmission is treatment of dysfunctional urinary bladder. This family of disorders is associated with the appearance of a purinergic component of neurogenic contractions. This component is an attractive target for drug development and targeting it may be a rewarding area of research.
ATP as a cotransmitter in the autonomic nervous system
2015, Autonomic Neuroscience: Basic and Clinical
Citation Excerpt :
Concomitantly, NA stimulates α1-adrenoceptors to elicit release of Ca2 + stores, via IP3 and the combined rise in cytoplasmic [Ca2 +], together with Ca2 + sensitisation (see below), induces contraction. Numerous studies in a variety of species using desensitisation of the P2X1 receptor by α,β-meATP or antagonists, such as suramin, PPADS and NF023, combined with α1-adrenoceptor blockade, show that the initial phasic component of neurogenic contractions of the vas deferens is predominantly purinergic, whilst the secondary, tonic phase is predominantly noradrenergic (see Sneddon et al., 1996, 1999). PPADS has also been used to identify a purinergic component in neurogenic contractions of human vas deferens (Banks et al., 2006).
The role of adenosine 5′-triphosphate (ATP) as a major intracellular energy source is well-established. In addition, ATP and related nucleotides have widespread extracellular actions via the ionotropic P2X (ligand-gated cation channels) and metabotropic P2Y (G protein-coupled) receptors. Numerous experimental techniques, including myography, electrophysiology and biochemical measurement of neurotransmitter release, have been used to show that ATP has several major roles as a neurotransmitter in peripheral nerves. When released from enteric nerves of the gastrointestinal tract it acts as an inhibitory neurotransmitter, mediating descending muscle relaxation during peristalsis. ATP is also an excitatory cotransmitter in autonomic nerves; 1) It is costored with noradrenaline in synaptic vesicles in postganglionic sympathetic nerves innervating smooth muscle preparations, such as the vas deferens and most arteries. When coreleased with noradrenaline, ATP acts at postjunctional P2X1 receptors to evoke depolarisation, Ca^2 + influx, Ca^2 + sensitisation and contraction. 2) ATP is also coreleased with acetylcholine from postganglionic parasympathetic nerves innervating the urinary bladder and again acts at postjunctional P2X1 receptors, and possibly also a P2X1 + 4 heteromer, to elicit smooth muscle contraction. In both cases the neurotransmitter actions of ATP are terminated by dephosphorylation by extracellular, membrane-bound enzymes and soluble nucleotidases released from postganglionic nerves. There are indications of an increased contribution of ATP to control of blood pressure in hypertension, but further research is needed to clarify this possibility. More promising is the upregulation of P2X receptors in dysfunctional bladder, including interstitial cystitis, idiopathic detrusor instability and overactive bladder syndrome. Consequently, these roles of ATP are of great therapeutic interest and are increasingly being targeted by pharmaceutical companies.
Influence of infection by Toxoplasma gondii on purine levels and E-ADA activity in the brain of mice experimentally infected mice
2014, Experimental Parasitology
Citation Excerpt :
ADP, AMP, adenosine, inosine, hypoxanthine, xanthine and uric acid are intermediate products that also participate in this cascade. Among the purines, the ATP is a well known neurotransmitter, as well as adenosine is considered as an important CNS modulator in mammals (Ralevic and Burnstock, 1998; Rathbone et al., 1999; Sitkovsky and Ohta, 2005; Sneddon et al., 1999; Burnstock, 2006; Desrosiers et al., 2007). The concentration of extracellular adenosine is regulated by the activity of a small group of important enzymes including ecto-adenosine deaminase (E-ADA; EC: 3.5.4.4), which catalyses the conversion of the adenosine into its inactive metabolite inosine.
The aim of this study was to assess the purine levels and E-ADA activity in the brain of mice (BALB/c) experimentally infected with Toxoplasma gondii. In experiment I (n = 24) the mice were infected with RH strain of T. gondii, while in experiment II (n = 36) they were infected with strain ME-49 of T. gondii. Our results showed that, for RH strain (acute phase), an increase in both periods in the levels of ATP, ADP, AMP, adenosine, hypoxanthine, xanthine (only on day 6 PI) and uric acid (only on day 6 PI). By the other hand, the RH strain led, on days 4 and 6 PI, to a reduction in the concentration of inosine. ME-49, a cystogenic strain, showed some differences in acute and chronic phase, since on day 6 PI the levels of ATP and ADP were increased, while on day 30 these same nucleotides were reduced. On day 60 PI, ME-49 induced a reduction in the levels of ATP, ADP, AMP, adenosine, inosine and xanthine, while uric acid was increased. A decrease of E-ADA activity was observed in brain on days 4 and 6 PI (RH), and 30 PI (ME-49); however on day 60 PI E-ADA activity was increased for infection by ME-49 strain. Therefore, it was possible to conclude that infection with T. gondii changes the purine levels and the activity of E-ADA in brain, which may be associated with neurological signs commonly observed in this disease.
Changes in purine levels associated with cellular brain injury in gerbils experimentally infected with Neospora caninum
2014, Research in Veterinary Science
The present study was carried out in order to assess the possible alterations in purine levels of brain, associated neuronal lesions in gerbils experimentally infected with Neospora caninum. For that, gerbils (Meriones unguiculatus) were inoculated with Nc-1 strain of N. caninum, composing two different experiments: Experiment I (EI) and experiment II (EII), where purine levels were measured along with the histopathologic study, on days 7 (EI), 15 and 30 (EII), post-infection (PI). As a result, it was possible to observe that the purine levels (ATP, ADP, AMP, adenosine, inosine and xanthine) in brain in EI are significantly reduced (p < 0.05), while in EII we faced a different pattern, since in the majority the purine levels were significantly increased (p < 0.05) on days 15 (ATP, AMP, adenosine, hypoxanthine and xanthine) and 30 PI (ATP, ADP, AMP, adenosine, and uric acid). Results of brain histopathology did not show histological lesion in animals of EI; however, in gerbils of EII it was possible to verify that the alterations (lesions) were more pronounced in gerbils evaluated on day 30 PI when compared to day 15 PI. Therefore, it was possible to conclude that the purine levels in brain were altered in both experiments, concomitant with the histopathological injuries observed in EII.
Differentiating connexin hemichannels and pannexin channels in cellular ATP release
2014, FEBS Letters
Citation Excerpt :
The biological relevance for adenine nucleotides acting as autocrine/paracrine signaling molecules is evident by the medley of purinergic receptor subtypes that are differentially expressed across cell types, the extracellular expression of nucleotidases whose activity fine tunes the abundance of ATP outside of the cell and the ubiquitous presence of ATP in all cells in the body, providing a pool of agonist for the initiation of purinergic signaling cascades in all aspects of human physiology. Indeed, purinergic signaling has been implicated in numerous physiological processes, including vascular tone and blood pressure regulation [1–7], respiratory control [8–10], and neurotransmission [11–14], as well as a number of pathologies including inflammation [15–18], atherosclerosis [19,20], cancer [21–24], and neurological disorders [25,26]. Two broad families of purinergic receptors have been identified to date, termed P1 and P2 receptors (for an extensive review on purinergic receptors see [27]).
Adenosine triphosphate (ATP) plays a fundamental role in cellular communication, with its extracellular accumulation triggering purinergic signaling cascades in a diversity of cell types. While the roles for purinergic signaling in health and disease have been well established, identification and differentiation of the specific mechanisms controlling cellular ATP release is less well understood. Multiple mechanisms have been proposed to regulate ATP release with connexin (Cx) hemichannels and pannexin (Panx) channels receiving major focus. However, segregating the specific roles of Panxs and Cxs in ATP release in a plethora of physiological and pathological contexts has remained enigmatic. This multifaceted problem has arisen from the selectivity of pharmacological inhibitors for Panxs and Cxs, methodological differences in assessing Panx and Cx function and the potential compensation by other isoforms in gene silencing and genetic knockout models. Consequently, there remains a void in the current understanding of specific contributions of Panxs and Cxs in releasing ATP during homeostasis and disease. Differentiating the distinct signaling pathways that regulate these two channels will advance our current knowledge of cellular communication and aid in the development of novel rationally-designed drugs for modulation of Panx and Cx activity, respectively.
Influence of experimental canine ehrlichiosis on the E-ADA activity and purine levels in serum and possible functional correlations with pathogenesis
2013, Veterinary Microbiology
Citation Excerpt :
ADP, AMP, adenosine, inosine, hypoxanthine and xanthine also participate on this cascade (Ralevic and Burnstock, 2003; Rathbone et al., 1999; Desrosiers et al., 2007). Purines play different vital functions in mammals, acting on neurotransmission, neuromodulation, coagulation and inflammation (Sneddon et al., 1999; Burnstock, 2006; Desrosiers et al., 2007). The ATP and adenosine are notable for their involvement in neurotransmission and immunological responses (Agresti et al., 2005; Bours et al., 2006).
The aim of this study was to evaluate adenosine deaminase activity and purines levels in serum of dogs experimentally infected by Ehrlichia canis. Banked serum samples of dogs divided into two groups with five animals each: healthy animals and animals infected by E. canis. The concentration of purines (adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), adenosine, inosine, hypoxanthine, xanthine and uric acid), and adenosine deaminase (E-ADA) activity in sera were evaluated. Samples were collected on days 12 and 30 post-infection (PI). The E-ADA activity showed a significant reduction on day 12 PI, and increased on day 30 PI in dogs infected with E. canis. On day 12, an increase in seric concentration of ATP, ADP and adenosine was verified, and different levels of hypoxanthine, xanthine and uric acid had a drastic reduction in infected compared healthy dogs (P < 0.05). However, on day 30 PI, the levels of seric ADP and AMP decreased, unlike the concentration of xanthine and uric acid that increased significantly in infected dogs (P < 0.05). Therefore, the activity of E-ADA and purine levels are altered in experimental canine ehrlichiosis, probably with the purpose of modulating the pathogenesis of the disease related to immune response, oxidative stress and coagulation disorders in acute phase.

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Chapter 2 Modulation of purinergic neurotransmission

Publisher Summary

Purinoceptors: Are there families of P2X and P2Y purinoceptors?

Pharmac. Ther.

Electrical and mechanical responses of guinea-pig bladder muscle to nerve stimulation

Br. J. Pharmacol.

Identification of competitive antagonists of the P2Y1 receptor

Mol. Pharmacol.

New structural motif for ligand-gated ion channels defined by an ionotropic ATP receptor

Nature

Pharmacological and biochemical analysis of FPL 67156, a novel, selective inhibitor of ecto ATPase

Br. J. Pharmacol.

ATP-mediated synaptic currents in the central nervous system

Nature

Characterization of P2-purinoceptors in the smooth muscle of the rat tail artery: A comparison between contractile and electrophysiological responses

Br. J. Pharmacol.

Towards a revised nomenclature for P1 and P2 receptors

Trend Pharm. Sci.

Neuromuscular transmission in the gastrointestinal tract

Relationship between nitric oxide and vasoactive intestinal polypeptide in enteric inhibitory neurotransmission

Neuropharmacology

An ecto-ATPase and an ecto-ATP diphosphohydrolase are expressed in rat brain

Neuropharmacology

Painful connection for ATP

Nature

Inhibition of ecto-ATPase and Ca-ATPase in rat vas deferens by P2-purinoceptor antagonists

Br. J. Pharmacol.

Complementary DNA cloning and sequencing of the chicken muscle ecto-ATPase

J. Biol. Chem.

Evidence for ATP as a cotransmitter in dog mesenteric artery

Eur. J. Pharmacol.