Rapid communicationP2 purinoceptors modulating noradrenaline release from sympathetic neurons in culture
Abstract
ATP (1 mM) inhibited, whereas 2-methylthio-ATP (30 μM), a P2Y-selective purinoceptor agonist, increased electrically evoked release of [3H]noradrenaline from chick sympathetic neurons. The P2X-selective purinoceptor agonist α,β-methylene-ATP (30 μM) had no effect. The ATP-induced inhibition of release as well as the facilitation caused by 2-methylthio-ATP was not affected by the selective adenosine (P1) receptor antagonist 8-(p-sulfophenyl)-theophylline (8-PST; 100 μM), but completely prevented by the non-selective P2 antagonist suramin (300 μM). The present data reveal a dual regulation of noradrenaline release from sympathetic neurons. Facilitation seems to be mediated by a P2Y purinoceptor, whereas inhibition is caused by a P2 purinoceptor which needs further subtype characterization.
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Cited by (29)
Stimulation of mouse cultured sympathetic neurons by uracil but not adenine nucleotides
2001, NeuroscienceCultured neurons from the paravertebral sympathetic chain of rats possess excitatory P2X as well as excitatory uracil nucleotide-sensitive P2Y receptors. Preliminary observations had indicated that the analogous neurons of mice lacked P2X receptors. This difference was now investigated. Thoracolumbar sympathetic neurons from one- to three-day-old mice were cultured for seven days. When the neurons were preincubated with [3H]noradrenaline and then superfused, ATP failed to cause any change in tritium outflow. UTP (3–300 μM) and UDP (30–100 μM), in contrast, caused marked increases, and so did nicotine (3–100 μM). The effect of UTP was not changed by suramin but abolished by tetrodotoxin and in the absence of calcium. The effect of nicotine was antagonized by hexamethonium and also abolished by tetrodotoxin and in the absence of calcium. Pre-exposure to UDP prevented the effect of UTP. In neurons studied by means of whole-cell patch-clamp techniques under current clamp, ATP lacked any effect. UTP (100 μM), UDP (100 μM) and nicotine (10 μM) caused depolarization accompanied by action potentials. Pre-exposure to UDP prevented the effect of UTP. In neurons studied under voltage clamp, ATP, UTP and UDP failed to cause any detectable current. Nicotine (10 μM), in contrast, elicited inward currents. Neither UTP nor UDP reduced the M-type potassium outward current.
These results demonstrate a pronounced difference between cultured sympathetic neurons from the mouse and the rat paravertebral chain. Neurons from both species possess the nicotinic acetylcholine receptor. Neurons from both species also possess uracil nucleotide-sensitive P2Y receptors which, when activated, mediate depolarization, action potential firing and noradrenaline release; these effects are not due to inhibition of M-type potassium channels. Only the rat but not the mouse neurons, however, possess P2X receptors which, when activated, mediate cation entry, depolarization, action potential generation and transmitter release. The absence of functional P2X receptors makes the mouse neurons suitable for further study of the uracil nucleotide-sensitive P2Y receptors.
ATP as a presynaptic modulator
2000, Life SciencesThere is considerable evidence that ATP acts as a fast transmitter or co-transmitter in autonomic and sensory nerves mostly through activation of ionotropic P2X receptors but also through metabotropic P2Y receptors. By analogy, the observations that ATP is released from stimulated central nervous system (CNS) nerve terminals and that responses to exogenously added ATP can be recorded in central neurons, lead to the proposal that ATP might also be a fast transmitter in the CNS. However, in spite of the robust expression of P2 receptor mRNA and binding to P2 receptors in the CNS, the demonstration of central purinergic transmission has mostly remained elusive. We now review evidence to suggest that ATP may also act presynaptically rather than solely postsynaptically in the nervous system.
P2-receptors controlling neurotransmitter release from postganglionic sympathetic neurones
1999, Progress in Brain ResearchThis chapter discusses the properties and the functional roles of P2-receptors present on postganglionic sympathetic neurons. A physiological role is well established for release inhibiting P2-receptors located at the axon terminals of postganglionic sympathetic neurons. These presynaptic P2-receptors are activated by cotransmitter ATP and operate as a kind of autoreceptor mediating a feedback inhibition of ongoing action potential evoked sympathetic transmitter release. In addition to release-modulating P2-receptors, postganglionic sympathetic neurons possess P2-receptors, activation of which causes the generation of action potentials and subsequently transmitter release. Excitatory P2-receptors located at the nerve cell bodies or dendrites of postganglionic sympathetic neurons have been proposed to be involved in fast synaptic neuro-neural transmission in sympathetic ganglia. Sympathetic neurons cultured from rat paravertebral ganglia possess two different subtypes of excitatory P2-receptors. Activation of both receptors induced the generation of action potentials and transmitter release. One receptor is an adenine nucleotide sensitive P2X-receptor. The other receptor is activated by uracil nucleotides and belongs most likely to the group of G-protein-coupled P2Y-receptors.
Differences in the mode of stimulation of cultured rat sympathetic neurons between ATP and UDP
1997, NeuroscienceReceptors controlling transmitter release from sympathetic neurons in vitro
1997, Progress in NeurobiologyPrimary cultures of postganglionic sympathetic neurons were established more than 30 years ago. More recently, these cultures have been used to characterize various neurotransmitter receptors that govern sympathetic transmitter release. These receptors may be categorized into at least three groups: (1) receptors which evoke transmitter release; (2) receptors which facilitate; (3) receptors which inhibit, depolarization-evoked release. Group (1) comprises nicotinic and muscarinic acetylcholine receptors, P2X purinoceptors and pyrimidinoceptors. Group (2) currently harbours β-adrenoceptors, P2 purinoceptors, receptors for PACAP and VIP, as well as prostanoid EP1 receptors. In group (3), muscarinic cholinoceptors, α2- and β-adrenoceptors, P2 purinoceptors, and receptors for the neuropeptides NPY, somatostatin (SRIF1) and LHRH, as well as opioid (δ and κ) receptors can be found. Receptors which regulate transmitter release from neurons in cell culture may be located either at the somatodendritic region or at the sites of exocytosis, i.e. the presynaptic specializations of axons. Most of the receptors that evoke release are located at the soma. There, ionotropic receptors cause depolarizations to generate action potentials which then trigger Ca2+-dependent exocytosis at axon terminals. The signalling mechanisms of metabotropic receptors which evoke release still remain to be identified. Receptors which facilitate depolarization-evoked release appear to be located preferentially at presynaptic sites and presumably act via an increase in cyclic AMP. Receptors which inhibit stimulation evoked release are also presynaptic origin and most commonly rely on a G protein-mediated blockade of voltage-gated Ca2+ channels.
Results obtained with primary cell cultures of postganglionic sympathetic neurons have now supplemented previous data about neurotransmitter receptors involved in the regulation of ganglionic as well as sympatho-effector transmission. In the future, this technique may prove useful to identify yet unrecognized receptors which control the output of the sympathetic nervous system and to elucidate underlying signalling mechanisms. © 1997 Elsevier Science Ltd. All Rights Reserved.
Modulation of neural ATP release through presynaptic receptors
1996, Seminars in the NeurosciencesNeural release of ATP can be elicited through or modulated through presynaptic receptors, as is known for classical transmitter substances. Activation of presynaptic nicotinic and serotonin receptors induces ATP release from postganglionic sympathetic axons. Inhibition of depolarization-evoked ATP release from these axons is mediated by, e.g. α2- and β2-adrenoceptors, adenosine A1-receptors and receptors for prostaglandin E2, neuropeptide Y and atrial natriuretic peptide. Enhancement of release is mediated by receptors for angiotensin and endothelin-3. Whether presynaptic P2-purinoceptors affect neural ATP release is unknown. A1-Receptors also mediate an inhibition of ATP release from cholinergic axons. Activation of some (e.g. neuropeptide Y) receptors causes an identical change in cotransmitter release. In other cases there is evidence for a differential modulation. A1-Receptors, for example, affect ATP release more markedly than noradrenaline release. The mechanisms causing differential modulation of cotransmitter release remain to be identified.