Prejunctional Adenosine and ATP Receptors (original) (raw)
Related papers
The Journal of Physiology, 1986
1. Adenosine and several of its analogues produced a concentration-dependent shortening of calcium-dependent action potential (c.a.p.) duration of mouse dorsal root ganglion (d.r.g.) neurones in dissociated cell culture. The following rank order of potency was obtained: N6-(L-phenylisopropyl)adenosine > N6-(D-phenylisopropyl)adenosine > N6-cyclohexyladenosine > 2-chloroadenosine > 1-methylisoguanosine > adenosine. Effects of adenosine agonists on c.a.p. duration were blocked by methylxanthine adenosine antagonists. Adenosine monophosphate (AMP) and cyclic AMP shortened c.a.p.s in d.r.g. neurones, while ATP also depolarized cells. 2. Voltage-clamp analysis revealed that the effect arose from reduction of a voltage-dependent calcium conductance. Adenosine agonists reduced depolarizationevoked inward currents but did not alter membrane conductance following blockade of calcium channels by cadmium. Additionally, adenosine reduced the instantaneous current-voltage slope (chord conductance) during step commands that produced maximal activation of voltage-dependent calcium conductance. 3. If effects of adenosine on neuronal somata and synaptic terminals are similar, adenosine agonists may inhibit neurotransmitter release in the central nervous system by inhibiting a voltage-dependent calcium conductance. Since effects of adenosine agonists did not correspond with their relative potencies as modulators of adenylate cyclase activity or inhibitors of neurotransmitter release in peripheral tissues, a novel adenosine receptor may be involved in regulation of this conductance.
The Journal of Physiology, 2000
Magnocellular neurones in the hypothalamic supraoptic nucleus (SON) synthesize arginine vasopressin and oxytocin. These peptides are released into the systemic circulation from axon terminals located in the neurohypophysis, and the released amount is closely related to the electrical activity of SON neurones (Bourque, 1991; Leng & Brown, 1997). This electrical activity is regulated by humoral factors and synaptic neurotransmitters/ neuromodulators, such as glutamate and ã_aminobutyric acid, various peptides and other physiological active substances including purinergic agents (Hatton, 1990; Brann, 1995; Shibuya et al. 1999). In various regions of the mammalian central nervous system (CNS), adenosine is well known to act as a neuro-transmitterÏneuromodulator (Fredholm & Dunwiddie, 1988). Adenosine modulates neural excitability and acts as a neural sleep factor in basal forebrain and mesopontine cholinergic neurones (Rainnie et al. 1994), as an endogenous anticonvulsant in the hippocampus and amygdala (Dragunow, 1988), as a modulator of LTP in the hippocampus (de Mendon ca & Ribeiro, 1994) and as a neuroprotective agent in the hippocampus (Dragunow & Faull, 1988). At present, classification of adenosine receptors is based on both their protein sequences and their affinity for a variety of ligands (Fredholm et al. 1994). Four subtypes of adenosine receptor have been cloned and pharmacologically characterized: A1, A2a, A2b and A× receptors. A1 and A× receptors are thought to be coupled to Gé andÏor Gï proteins, while A2a and A2b are coupled to Gs protein (Fredholm et al. 1994; Palmer & Stiles, 1995). The various effects of adenosine on neuronal activity are thought to occur through the modulation of Ca¥ channels andÏor K¤ channels (Fredholm & Dunwiddie, 1988; Fredholm et al. 1994; Palmer & Stiles, 1995). It has been reported that adenosine modulates voltage-dependent calcium channels (VDCCs) in the postsynaptic membrane of many different
Neuroscience Research, 1997
Adenosine inhibited the release of acetylcholine (ACh) evoked by high K + depolarization from synaptosomes isolated from the electric organ of the Japanese electric ray Narke japonica. The adenosine A 1 receptor agonist N 6-cyclohexyladenosine was an effective inhibitor. Conversely, in the presence of an A 1 receptor antagonist, 8-cyclopentyltheophylline, adenosine potentiated the release of ACh. The A 2 receptor agonist N 6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl] adenosine also facilitated the evoked ACh release. Thus, adenosine inhibits the evoked release of ACh via the A 1 receptor while it facilitates the release via the A 2 receptor. The EC 50 for inhibition and facilitation by adenosine was about 1 and 41 vM, respectively. There are three known types of calcium channels (N-, P/Q-and L-type) in synaptosomes. The effects of Ca 2 + channel type-specific blockers on the modulation of ACh release by adenosine A 1 or A 2 receptor activation revealed that inhibition by A 1 receptor activation was caused via inhibition of N-type calcium channels and the facilitative effects by A 2 receptor activation was mediated by potentiation of P-type calcium channels.
Transduction mechanism involving the presynaptic adenosine receptor at mouse motor nerve terminals
Neuroscience Letters, 1989
The inhibitory effect of 2-chloroadenosine on spontaneous quantal release of transmitter at the mouse neuromuscular junction was abolished after pretreating tissues either with pertussis toxin (PTX), or with HT, a protein kinase inhibitor. H7 alone caused a fall in miniature endplate potential (MEPP) frequency, but PTX did not. The results are consistent with the hypothesis that rates of neurotransmitter release are directly related to intraterminal cyclic AMP levels, and that these can be reduced by At adenosine receptor agonists through the mediation of a G~ protein.
Endogenous adenosine inhibits CNS terminal Ca2+ currents and exocytosis
Journal of Cellular Physiology, 2007
Bursts of action potentials (APs) are crucial for the release of neurotransmitters from dense core granules. This has been most definitively shown for neuropeptide release in the hypothalamic neurohypophysial system (HNS). Why such bursts are necessary, however, is not well understood. Thus far, biophysical characterization of channels involved in depolarization-secretion coupling cannot completely explain this phenomenon at HNS terminals, so purinergic feedback mechanisms have been proposed. We have previously shown that ATP, acting via P2X receptors, potentiates release from HNS terminals, but that its metabolite adenosine, via A 1 receptors acting on transient Ca 2þ currents, inhibit neuropeptide secretion. We now show that endogenous adenosine levels are sufficient to cause tonic inhibition of transient Ca 2þ currents and of stimulated exocytosis in HNS terminals. Initial non-detectable adenosine levels in the static bath increased to 2.9 mM after 40 min. These terminals exhibit an inhibition (39%) of their transient inward Ca 2þ current in a static bath when compared to a constant perfusion stream. CPT, an A 1 adenosine receptor antagonist, greatly reduced this tonic inhibition. An ecto-ATPase antagonist, ARL-67156, similarly reduced tonic inhibition, but CPT had no further effect, suggesting that endogenous adenosine is due to breakdown of released ATP. Finally, stimulated capacitance changes were greatly enhanced (600%) by adding CPT to the static bath. Thus, endogenous adenosine functions at terminals in a negativefeedback mechanism and, therefore, could help terminate peptide release by bursts of APs initiated in HNS cell bodies. This could be a general mechanism for controlling transmitter release in these and other CNS terminals.
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.
Ionic mechanism of action of adenosine on the rat superior cervical ganglion
Journal of Autonomic Pharmacology, 1993
The ionic mechanism responsible for hyperpolarization of the rat superior cervical ganglion (SCG) and depression of the depolarizing response to muscarine by adenosine was studied using an extracellular grease-gap recording technique. 2 Both the hyperpolarizations to adenosine and 2-chloroadenosine and the depression of the response to muscarine by adenosine were potentiated in reduced external calcium (Caz+). Hyperpolarizations to adenosine were either unaltered or potentiated in the presence of the dihydropyridine Ca2+ channel antagonists, nitrendipine or (+)PN200 I 10 respectively. Hyperpolarizations to adenosine were unaltered by inorganic CaZ + channel antagonists except for cobalt, which also antagonized hyperpolarizations to carbachol and depolarizations to muscarine. 3 Hyperpolarizations to adenosine were unaltered in nominally magnesium (Mg2+)-free or in reduced external chloride (Cl-) media. When sodium ions (Na+) were replaced by lithium ions (Li+) maximal responses to adenosine were initially enhanced, returning to pretreatment levels and subsequently reduced in their duration. In contrast, responses to adenosine were significantly enhanced in nominally potassium (K+)-free medium and reduced upon doubling the extracellular K+. 4 Hyperpolarisations were enhanced in the presence of the K + channel antagonists, 4-aminopyridine and 3,4-diaminopyridine, and reduced by a low concentration (2 mM) of tetraethylammonium (TEA), but not in 10 mM TEA. 5 The results support the hypothesis that adenosine-mediated hyperpolarization of postganglionic neurones of the rat SCG is by a Caz+-independent mechanism and is probably mediated via an increase of a K+ current. The results also indicate that adenosine-induced hyperpolarizations of the rat SCG are independent of the presence of extracellular magnesium.
European Journal of Neuroscience, 2003
Corelease of ATP with ACh from motor endings suggests a physiological role for ATP in synaptic transmission. We previously showed that, on skeletal muscle, ATP directly inhibited ACh release via presynaptic P2 receptors. The receptor identi®cation (P2X or P2Y) and its transduction mechanism remained, however, unknown. In the present study using the voltage-clamp technique we analyzed the properties of presynaptic ATP receptors and subsequent effector mechanisms. ATP or adenosine presynaptically depressed multiquantal end-plate currents, with longer latency for ATP action. ATPgS, agonist at P2X receptors, or Bz-ATP, agonist at P2X 7 receptors, were ineffective. The action of ATP was prevented by suramin and unchanged by PPADS or TNP-ATP, antagonists of P2X receptors, or RB-2, a blocker of certain P2Y receptors. The depressant action of ATP was reproduced by UTP, metabotropic P2Y receptor agonist. Pertussis toxin (PTX), antagonist of G i/o -proteins, and inhibitors of phosphatidylcholine speci®c PLC (D609) and PKC (staurosporine or chelerythrine) prevented the effect of ATP while blockers of PLA 2 (OBAA) and COX (aspirin or indomethacin) attenuated it. Inhibitors of phosphatidylinositide-speci®c PLC (U73122), guanylylcyclase (ODQ), PKA (Rp-cAMPS) or PLD (1-butanol) did not affect the action of ATP. No inhibitor of second messengers (except PTX) changed the action of adenosine. Our data indicate, for motor nerve endings, the existence of inhibitory P2Y receptors coupled to multiple intracellular cascades including phosphatidylinositide-speci®c PLC/PKC/PLA 2 /COX. This divergent presynaptic P2 signalling (unlike the single effector mechanism for P1 receptors) could provide feedback inhibition of transmitter release and perhaps be involved in presynaptic plasticity.
The Journal of Physiology, 2002
Effects of adenosine on voltage-gated Ca 2+ channel currents and on arginine vasopressin (AVP) and oxytocin (OT) release from isolated neurohypophysial (NH) terminals of the rat were investigated using perforated-patch clamp recordings and hormone-specific radioimmunoassays. Adenosine, but not adenosine 5‚-triphosphate (ATP), dose-dependently and reversibly inhibited the transient component of the whole-terminal Ba 2+ currents, with an IC 50 of 0.875 mM. Adenosine strongly inhibited, in a dose-dependent manner (IC 50 = 2.67 mM), depolarization-triggered AVP and OT release from isolated NH terminals. Adenosine and the N-type Ca 2+ channel blocker v-conotoxin GVIA, but not other Ca 2+ channel-type antagonists, inhibited the same transient component of the Ba 2+ current. Other components such as the L-, Q-and R-type channels, however, were insensitive to adenosine. Similarly, only adenosine and v-conotoxin GVIA were able to inhibit the same component of AVP release. A 1 receptor agonists, but not other purinoceptor-type agonists, inhibited the same transient component of the Ba 2+ current as adenosine. Furthermore, the A 1 receptor antagonist 8-cyclopentyltheophylline (CPT), but not the A 2 receptor antagonist 3, 7-dimethyl-1-propargylxanthine (DMPGX), reversed inhibition of this current component by adenosine. The inhibition of AVP and OT release also appeared to be via the A 1 receptor, since it was reversed by CPT. We therefore conclude that adenosine, acting via A 1 receptors, specifically blocks the terminal N-type Ca 2+ channel thus leading to inhibition of the release of both AVP and OT.