Chapter 23 Purinergic regulation of acetylcholine release (original) (raw)
Related papers
Pfl�gers Archiv European Journal of Physiology, 1993
The independent release of adenosine and adenine nucleotides upon electrical stimulation was studied in the innervated sartorius muscle of the frog after blockade of the extracellular catabolism of adenosine monophosphate (AMP) through exo-AMP deaminase and ecto-5'-nucleotidase. Nerve stimulation (30 rain, 0.2Hz) induced the release of both adenosine (19 • 3 pmol) and adenine nucleotides (101 • 7 pmol). Experiments performed in the presence of tubocurarine (5 gM) to prevent purine release due to nerve-evoked muscle twitching, or under direct stimulation of the muscle in low calcium solutions to prevent pre-synaptic release of purines, showed that there was an evoked release of adenosine and adenine nucleotides both from the nerve endings and from the twitching muscle fibres. Removal of ecto-5'-nucleotidase inhibition shows that the catabolism of adenine nucleotides released during stimulation contributes in about 50% to the amount of endogenous extracellular adenosine. When only one of the enzymes catabolizing AMP (ecto-5"-nucleotidase or exo-AMP deaminase) was inhibited, the evoked release of adenine nucleotides was undetectable, suggesting that each enzyme is able to catabolize all the AMP formed from adenine nucleotides released upon stimulation. It is concluded that the concentration of endogenous extracellular adenosine is under the control of the relative activities of exo-AMP deaminase and ecto-5'-nucleotidase.
Modulatory Roles of ATP and Adenosine in Cholinergic Neuromuscular Transmission
International Journal of Molecular Sciences, 2020
A review of the data on the modulatory action of adenosine 5’-triphosphate (ATP), the main co-transmitter with acetylcholine, and adenosine, the final ATP metabolite in the synaptic cleft, on neuromuscular transmission is presented. The effects of these endogenous modulators on pre- and post-synaptic processes are discussed. The contribution of purines to the processes of quantal and non-quantal secretion of acetylcholine into the synaptic cleft, as well as the influence of the postsynaptic effects of ATP and adenosine on the functioning of cholinergic receptors, are evaluated. As usual, the P2-receptor-mediated influence is minimal under physiological conditions, but it becomes very important in some pathophysiological situations such as hypothermia, stress, or ischemia. There are some data demonstrating the same in neuromuscular transmission. It is suggested that the role of endogenous purines is primarily to provide a safety factor for the efficiency of cholinergic neuromuscular ...
ATP but not adenosine inhibits nonquantal acetylcholine release at the mouse neuromuscular junction
European Journal of Neuroscience, 2001
The postsynaptic membrane of the neuromuscular synapse treated with antiacetylcholinesterase is depolarized due to nonquantal release of acetylcholine (ACh) from the motor nerve ending. This can be demonstrated by the hyperpolarization produced by the application of curare (H-effect). ATP (1 Q 10 ±5 M) decreased the magnitude of the H-effect from 5 to 1.5 mV. The membrane input resistance and the ACh sensitivity were unchanged, and so changes in these cannot explain the ATP effect. Adenosine alone was without effect on the nonquantal release. On the other hand, both ATP and adenosine depressed the frequency of spontaneous miniature endplate potentials, to 56% and 43% respectively. The protein kinase A inhibitor Rp-cAMP or the guanylyl cyclase inhibitor 1H-[1,2,4]oxidiazolo[4,3-a]quinoxalin-1-one did not affect the inhibitory in¯uence of ATP on the H-effect, whereas staurosporine, an inhibitor of protein kinase C, completely abolished the action of ATP. Suramin, an ATP antagonist, enhanced the H-effect to 8.6 mV and, like staurosporine, prevented the inhibitory effect of ATP. ATP thus suppresses the nonquantal release via a direct action on presynaptic metabotropic P2 receptors coupled to protein kinase C, whilst adenosine exerts its action mainly by affecting the mechanisms underlying quantal release. These data, together with earlier evidence, show that nonquantal release of ACh can be modulated by several distinct regulatory pathways, in particular by endogenous substances which may or may not be present in the synaptic cleft at rest or during activity.
Background and purpose: Nitric oxide (NO) production and depression of neuromuscular transmission are closely related, but little is known about the role of L-citrulline, a co-product of NO biosynthesis, on neurotransmitter release. Experimental approach: Muscle tension recordings and outflow experiments were performed on rat phrenic nervehemidiaphragm preparations stimulated electrically. Key results: L-citrulline concentration-dependently inhibited evoked [ 3 H]ACh release from motor nerve terminals and depressed nerve-evoked muscle contractions. The NO synthase (NOS) substrate, L-arginine, and the NO donor, 3-morpholinosydnonimine chloride (SIN-1), also inhibited [ 3 H]ACh release with a potency order of SIN-14L-arginine4L-citrulline. Co-application of L-citrulline and SIN-1 caused additive effects. NOS inactivation with N o -nitro-L-arginine prevented L-arginine inhibition, but not that of L-citrulline. The NO scavenger, haemoglobin, abolished inhibition of [ 3 H]ACh release caused by SIN-1, but not that caused by L-arginine. Inactivation of guanylyl cyclase with 1H-[1,2,4]oxadiazolo[4,3a]quinoxalin-1-one (ODQ) fully blocked SIN-1 inhibition, but only partially attenuated the effects of L-arginine. Reduction of extracellular adenosine accumulation with adenosine deaminase or with the nucleoside transport inhibitor, S-(p-nitrobenzyl)-6-thioinosine, attenuated the effects of L-arginine and L-citrulline, while not affecting inhibition by SIN-1. Similar results were obtained with the selective adenosine A 1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine. L-citrulline increased the resting extracellular concentration of adenosine, without changing that of the adenine nucleotides. Conclusions and implications: NOS catalyses the formation of two neuronally active products, NO and L-citrulline. While, NO may directly reduce transmitter release through stimulation of soluble guanylyl cyclase, the inhibitory action of L-citrulline may be indirect through increasing adenosine outflow and subsequently activating inhibitory A 1 receptors.
At synapses, ATP is released and metabolised through ecto-nucleotidases forming adenosine, which modulates neurotransmitter release through inhibitory A 1 or facilitatory A 2A receptors, according to the amounts of extracellular adenosine. Neuromuscular junctions possess an ecto-AMP deaminase that can dissociate extracellular ATP catabolism from adenosine formation. In this study we have investigated the pattern of ATP release and its conversion into adenosine, to probe the role of ecto-AMP deaminase in controlling acetylcholine release from rat phrenic nerve terminals. Nerve-evoked ATP release was 28 ± 12 pmol (mg tissue) _1 at 1 Hz, 54 ± 3 pmol (mg tissue) _1 at 5 Hz and disproportionally higher at 50 Hz (324 ± 23 pmol (mg tissue) _1 ). Extracellular ATP (30 mM) was metabolised with a half time of 8 ± 2 min, being converted into ADP then into AMP. AMP was either dephosphorylated into adenosine by ecto-5‚-nucleotidase (inhibited by ATP and blocked by 200 mM a,b-methylene ADP) or deaminated into IMP by ecto-AMP deaminase (inhibited by 200 mM deoxycoformycin, which increased adenosine formation). Dephosphorylation and deamination pathways also catabolised endogenously released adenine nucleotides, since the nerveevoked extracellular AMP accumulation was increased by either a,b-methylene ADP (200 mM) or deoxycoformycin (200 mM). In the presence of nitrobenzylthioinosine (30 mM) to inhibit adenosine transport, deoxycoformycin (200 mM) facilitated nerve-evoked [ 3 H]acetylcholine release by 77 ± 9 %, an effect prevented by the A 2A receptor antagonist, ZM 241385 (10 nM). It is concluded that, while ecto-5‚-nucleotidase is inhibited by released ATP, ecto-AMP deaminase activity transiently blunts adenosine formation, which would otherwise reach levels high enough to activate facilitatory A 2A receptors on motor nerve terminals.
On the site of action and inactivation of adenosine by the rat superior cervical ganglion
Journal of Autonomic Pharmacology, 1993
Using an extracellular recording technique, we have investigated the site of action of adenosine and muscarine on the rat superior cervical ganglion (SCG). The adenosine-induced hyperpolarization and muscarine-induced depolarization of ganglia were localized to the cell bodies of the ganglia. Responses to muscarine and adenosine were larger when recorded via the internal carotid nerve (ICN) compared with the external carotid nerve. Depression of the response to muscarine by adenosine was similar for both nerve trunks. 2 The effects of adenosine and cyclic nucleotides on the d.c. potential and the depolarization to muscarine were examined by recording via the ICN. Adenosine at concentrations up to 1 mM produced concentration-dependent hyperpolarizations. Hyperpolarization induced by 1 00 p~ adenosine was unaffected by 1 ,LLM tetrodotoxin or the muscarinic M 1-receptor antagonist pirenzepine (0.3 p~). In contrast, hyperpolarizations to 100 ~L M adenosine were significantly reduced by 10 ~L M 8-phenytheophylline (5 5 t 7 pV vs 15 t 9 pV, P<O.OI, n = 4). Two agents known to increase intracellular CAMP, i.e. 8-bromocyclic-adenosine-3'-5'monophosphate (8BrcAMP) and isoprenaline, depolarized ganglia. Depolarizations to 100 nM mucarine were significantly depressed by adenosine (100 p~) by 26 k 2% (n= 6 l), but unaltered by 8BrcAMP or cyclic guanosine-3'-5'monophosphate. 3 Dipyridamole and hydroxy-nitro-benzylthioguanosine (inhibitors of adenosine transport) and erythro-6-amino-9-(2-hydroxy-3-nonyl)adenine (EHNA, an inhibitor of adenosine deaminase), potentiated the depression by adenosine of the response to muscarine, and the hyperpolarization to adenosine respectively. However, there was no evidence to support the hypothesis that there was spontaneous release of endogenous adenosine under the conditions of study, as dipyridamole or EHNA did not alter the control d.c. potential or the depolarization to muscarine. 4 It is concluded that the ability of adenosine to hyperpolarize and depress the response of the rat SCG to muscarine is due to the direct activation of postsynaptic somatodendritic P,-purinoceptors and unlikely to be mediated by an increase in intracellular CAMP. In addition the rat SCG has mechanisms for both the uptake and inactivation of adenosine.
Naunyn-Schmiedeberg's Archives of Pharmacology, 1993
1. The effect of adenosine or its stable analogues (2-chloroadenosine, CADO; 5'-N-ethylcarboxamidoadenosine, NECA; and N6-cyclopentyladenosine, CPA) on the release of [aH]-acetylcholine ([aH]-ACh), and on the development of force of contraction evoked by electrical stimulation of the nerve, were studied in the mouse phrenic nerve-hemidiaphragm preparation. Evidence was obtained that the release of ACh is subject to presynaptie modulation through presynaptic A~(P1)purinoceptors.
On the type of receptor involved in the inhibitory action of adenosine at the neuromuscular junction
British Journal of Pharmacology, 1985
The effects of adenosine and adenosine analogues (1‐N6‐phenylisopropyladenosine (1‐PIA), d‐N6‐phenylisopropyladenosine (d‐PIA), N6‐cyclohexyladenosine (CHA), N6‐methyladenosine, 5′‐N‐ethyl‐carboxamide adenosine (NECA) and 2‐chloroadenosine) on evoked endplate potentials (e.p.ps) and on twitch tension were investigated in innervated sartorius muscles of the frog. Adenosine and its analogues decreased, in a concentration‐dependent manner, the amplitude of both the e.p.ps and the twitch responses evoked by indirect stimulation. The order of potencies in decreasing twitch tension was: 1‐PIA, CHA, NECA > 2‐chloroadenosine > d‐PIA > n6‐methyladenosine, adenosine. 1‐PIA was about ten fold more potent than d‐PIA. None of the adenosine analogues tested affected the twitch responses of directly stimulated tubocurarine‐paralyzed muscles. In concentrations that did not modify neuromuscular transmission, theophylline and 8‐phenylth‐eophylline (8‐PT) but not isobutylmethylxanthine (IBMX)...
Adenosine Triphosphate (ATP) as a Neurotransmitter
Encyclopedia of Neuroscience, 2010
The molecule of adenosine 5 0 -triphosphate, ATP, was discovered in 1929 by Karl Lohman in Heidelberg and by Cyrus Hartwell Fiske and Yellapragada Sub-baRow at Harvard. In the same year, the role for purines and ATP as extracellular signaling molecules was also suggested by Drury and Szent-Gyö rgyi, who found that purines exert a potent negative chronotropic effect on the heart and trigger dilatation of coronary vessels. The signaling function of ATP in peripheral tissues was subsequently confirmed by numerous experiments.