Modulation of synaptic activity in Purkinje neurons by ATP (original) (raw)
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Neuropharmacology, 1999
P2X receptors present in cerebellar Purkinje cells have been studied by recording ATP-elicited [Ca 2 + ] i signals from immuno-identified (calbindin +) cells in culture using fura-2 microfluorescence. The [Ca 2 + ] i increases evoked by ATP were mimicked by 2MeSATP but not by a,b-meATP and other purinoceptor agonists. The selective P2X 1 antagonist diinosine pentaphosphate failed to inhibit ATP-elicited [Ca 2 + ] i transients, but suramin and PPADS rapidly and reversibly blocked the [Ca 2 + ] i responses to ATP and 2MeSATP. The IC 50 values for suramin and PPADS inhibition were 48.7 9 4.4 and 5.9 9 0.3 mM, respectively. Both antagonists blocked completely the signal elicited by ATP, revealing that there was not a separate antagonist-insensitive P2X receptor population in Purkinje cells. The effect of ATP was potentiated by Zn 2 + and H + ions. A one unit acidification from pH 7.4 to 6.4 enhanced by 172% the [Ca 2 + ] i transient elicited by an intermediate concentration of ATP. Conversely, alkalinization of the medium to pH 8.4 reduced the ATP response by 88%. This combination of pharmacological and modulatory properties indicates that endogenous P2X receptors present in Purkinje neurons are formed by P2X 2 subunits, rather than the more abundantly expressed P2X 4 purinoceptor subunits.
Enhancement of spontaneous synaptic activity in rat Purkinje neurones by ATP during development
The Journal of Physiology, 2005
The establishment of functional synaptic connections and activity is a pivotal process in the development of neuronal networks. We have studied the synaptic activity in the developing rat cerebellum, and the contribution mediated by purinergic receptors. The mean frequency of the spontaneous postsynaptic currents (sPSCs) recorded with the whole-cell patch-clamp technique from Purkinje neurones in acute brain slices at room temperature, increased fourfold from 4.4 ± 0.8 Hz at postnatal day 9/10 (n = 23) to 17.8 ± 1.6 Hz at postnatal day 17-20 (p17-p20; n = 113; P < 0.01). ATP, which increased the frequency of sPSCs by up to 100% (EC 50 = 18 µM) in the third postnatal week, started to modulate the synaptic activity during the second postnatal week, which was determined by three processes: (1) the appearance of functional ATP receptors during p10-p12, (2) the enhancement of the sPSC frequency by endogenous ATP release becoming apparent after inhibition of ecto-ATPases by 6-N ,N -diethyl-β,γ-dibromomethylene-D-adenosine-5-triphosphate (ARL67156; 50 µM) at p11-p12, and (3) with tonic stimulation of purinoceptors at p14, as revealed by the P2 receptor antagonist pyridoxal-phosphate-6-azophenyl-2 ,4 -disulphonic acid (PPADS, 10 µM). ATP had a similar effect at later stages (p24-p27) and at 35 • C. Our results suggest that endogenous release of ATP starts to enhance the synaptic activity in Purkinje neurones by the end of the second postnatal week.
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.
AJP: Regulatory, Integrative and Comparative Physiology, 2006
Song Z, Vijayaraghavan S, Sladek CD. ATP increases intracellular calcium in supraoptic neurons by activation of both P2X and P2Y purinergic receptors. increases intracellular calcium concentration ([Ca 2ϩ ]i) in supraoptic nucleus (SON) neurons in hypothalamo-neurohypophyseal system explants loaded with the Ca 2ϩ -sensitive dye, fura 2-AM. Involvement of P2X purinergic receptors (P2XR) in this response was anticipated, because ATP stimulation of vasopressin release from hypothalamo-neurohypophyseal system explants required activation of P2XRs, and activation of P2XRs induced an increase in [Ca 2ϩ ]i in dissociated SON neurons. However, the ATP-induced increase in [Ca 2ϩ ]i persisted after removal of Ca 2ϩ from the perifusate ([Ca 2ϩ ]o). This suggested involvement of P2Y purinergic receptors (P2YR), because P2YRs induce Ca 2ϩ release from intracellular stores, whereas P2XRs are Ca 2ϩpermeable ion channels. Depletion of [Ca 2ϩ ]i stores with thapsigargin (TG) prevented the ATP-induced increase in [Ca 2ϩ ]i in zero, but not in 2 mM [Ca 2ϩ ]o, indicating that both Ca 2ϩ influx and release of intracellular Ca 2ϩ contribute to the ATP response. Ca 2ϩ influx was partially blocked by cadmium, indicating a contribution of voltagegated Ca 2ϩ channels. PPADS (pyridoxal-phosphate-6-azophenyl-2Ј,4Ј-disulphonic acid), and iso-PPADS, P2XR antagonists, attenuated, but did not abolish, the ATP-induced increase in [Ca 2ϩ ]i. Combined treatment with PPADS or iso-PPADS and TG prevented the response. A cocktail of P2YR agonists consisting of UTP, UDP, and 2-methylthio-ADP increased [Ca 2ϩ ]i (with or without tetrodotoxin) that was markedly attenuated by TG. 2-Methylthio-ADP alone induced consistent and larger increases in [Ca 2ϩ ]i than UTP or UDP. MRS2179, a specific P2Y 1R antagonist, eliminated the response to ATP in zero [Ca 2ϩ ]o. Thus, both P2XR and P2YR participate in the ATP-induced increase in [Ca 2ϩ ]i, and the P2Y1R subtype is more prominent than P2Y 2R, P2Y4R, or P2Y6R in SON. calcium imaging; fura-2 acetoxymethyl ester; thapsigargin; pyridoxalphosphate-6-azophenyl-2Ј,4Ј-disulphonic acid; cadmium ATP ACTS AS A NEUROTRANSMITTER in the central and peripheral nervous system. It is copackaged with other neurotransmitters in synaptic vesicles, coreleased during exocytosis of those vesicles, and activates purinergic receptors (PR) located both pre-and postsynaptically . There are two major classes of PRs. P2X purinergic receptors (P2XRs) are ligand gated, nonselective cation channels that are highly permeable to Ca 2ϩ . P2Y purinergic receptors (P2YRs) are G protein-coupled receptors. Multiple subtypes of both classes of receptors have been cloned and classified as P2X 1-7 and P2Y 1-8 (19).
Electrophysiological effects of ATP on brain neurones
Journal of Autonomic Pharmacology, 1996
of P2 purinoceptors by the unmetabolized nucleotide or to the indirect activation of PI purinoceptors by the degradation product adenosine. 2 protein-coupled receptor (Pzy). Hence, the stimulation of Pzx purinoceptors leads to a cationic conductance increase, while the stimulation of PzU purinoceptors leads to a G protein-mediated opening or closure of potassium channels. 3 ATP may induce a calcium-dependent potassium current by increasing the intracellular Ca2+ concentration. This is due either to the entry of Ca2+ via P2x purinoceptors or to the activation of metabotropic PZY purinoceptors followed by signaling via the G protein/phospholipase C/inositol 1,4,5-trisphosphate (IP,) cascade. Eventually, IP3 releases Ca2+ from its intracellular pools. 4 There is no convincing evidence for the presence of PZu purinoceptors sensitive to both ATP and IJTP, or pyrimidinoceptors sensitive to UTP only, in the central nervous system (CNS). 5 ATP-sensitive PZX and PZy purinoceptors show a wide distribution in the CNS and appear to regulate important neuronal functions.
Adenosine and ATP receptors in the brain
Current topics in medicinal chemistry, 2011
There is a widespread presence of both adenosine (P1) and P2 nucleotide receptors in the brain on both neurones and glial cells. Adenosine receptors play a major role in presynaptic neuromodulation, while P2X receptors are involved in fast synaptic transmission and synaptic plasticity. P2Y receptors largely mediate presynaptic activities. Both P1 and P2 receptors participate in neurone-glia interactions. Purinergic signalling is involved in control of cerebral vascular tone and remodelling. Examples of the roles of purinoceptors in neuropathology involve: A 2A receptors in Parkinson's disease and epilepsy, P2 receptors in trauma, ischaemia, neuroinflammatory and neuropsychiatric disorders, and neuropathic pain.
Neuroscience Letters, 2001
Adenosine 5 H -triphosphate (ATP) stimulates a [Ca 21 ] i increase via speci®c ionotropic receptors, termed P2X receptors, in rat midbrain presynaptic terminals. A micro¯uorimetric technique enabled study of the [Ca 21 ] i increase in isolated single synaptic terminals, showing that 33.4^2.5% of them responded to ATP. Immunological studies carried out, after functional studies, with speci®c anti-P2X receptor subunit antibodies showed only positive labelling with anti-P2X 3 antibodies in 23.5^1.7% of the terminals. All positively P2X 3 labelled synaptic terminals responded to ATP. Nevertheless, not all of them responded to a,b-meATP, these representing 6.7^1.5% of the total. In addition, 9.8^2.3% of the terminals responded to ATP but exhibit negative P2X 3 -labelling. These results demonstrate the existence of a heterogeneous population of ionotropic ATP receptors at the presynaptic level. q
Signalling via ATP in the nervous system
Trends in neurosciences, 1994
Strong evidence has been provided that ATP can act as a transmitter not only in smooth muscle but also in peripheral ganglia and in brain. The cloning and molecular identification of two putative ATP receptors supports the previously established pharmacological receptor classifications. This review places into perspective the evidence for ATP as a neural signalling substance by examining sites of storage, release and hydrolysis, as well as potential actions and targets. The action of ATP is related to that of the nucleoside adenosine, and the potential of additional nucleotides to function as neural messenger is examined briefly.