Adenosine A1 and A2A receptor‐mediated modulation of acetylcholine release in the mice neuromuscular junction

García, Neus; Priego, Mercedes; Obis, Teresa; Santafé, Manel M.; Tomàs, Marta; Besalduch, Núria; Lanuza, María A.; Tomàs, Josep

doi:10.1111/ejn.12220

Cited by 35 publications

(69 citation statements)

References 61 publications

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“…M 2 receptors promote release in all nerve endings independently of their ACh release level or maturation state, whereas an M 1 -and M 4 -mediated reduction in release is observed in the weakest endings on polyinnervated dual junctions [14-16, 18, 27, 32] . Similarly, ARs are present in the motor terminals of the newborn and adult NMJs [35,36] . In the adult, the extent to which inhibitory A 1 R and excitatory A 2A R modulate the evoked release of ACh [37] seems to depend on the extracellular concentration of adenosine.…”

Section: Discussionmentioning

confidence: 99%

“…In the adult, ARs and mAChRs heavily depend on each other to modulate ACh release by sharing the PKC and PKA pathways [35,22] . The influx of external Ca 2+ required for Ca 2+ -triggered exocytosis and the fast mode of endocytosis seems to be promoted with the involvement of the presynaptic mAChR [34] , and interaction with the AR [44] but also with the BDNF-TrkB receptor pathway [23,43] .…”

Section: Relation Between Machrs and Arsmentioning

confidence: 99%

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Synergistic Action of Presynaptic Muscarinic Acetylcholine Receptors and Adenosine Receptors in Developmental Axonal Competition at the Neuromuscular Junction

Nadal

García²,

Hurtado³

et al. 2016

Dev Neurosci

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The development of the nervous system involves the initial overproduction of synapses, which promotes connectivity. Hebbian competition between axons with different activities leads to the loss of roughly half of the overproduced elements and this refines connectivity. We used quantitative immunohistochemistry to investigate, in the postnatal day 7 (P7) to P9 neuromuscular junctions, the involvement of muscarinic receptors (muscarinic acetylcholine autoreceptors and the M₁, M₂, and M₄ subtypes) and adenosine receptors (A₁ and A_2A subtypes) in the control of axonal elimination after the mouse levator auris longus muscle had been exposed to selective antagonists in vivo. In a previous study we analyzed the role of each of the individual receptors. Here we investigate the additive or occlusive effects of their inhibitors and thus the existence of synergistic activity between the receptors. The main results show that the A_2A, M₁, M₄, and A₁ receptors (in this order of ability) delayed axonal elimination at P7. M₄ produces some occlusion of the M₁ pathway and some addition to the A₁ pathway, which suggests that they cooperate. M₂ receptors may modulate (by allowing a permissive action) the other receptors, mainly M₄ and A₁. The continued action of these receptors (now including M₂ but not M₄) finally promotes axonal loss at P9. All 4 receptors (M₂, M₁, A₁, and A_2A, in this order of ability) are necessary. The M₄ receptor (which in itself does not affect axon loss) seems to modulate the other receptors. We found a synergistic action between the M₁, A₁, and A_2A receptors, which show an additive effect, whereas the potent M₂ effect is largely independent of the other receptors (though can be modulated by M₄). At P9, there is a full mutual dependence between the A₁ and A_2A receptors in regulating axon loss. In summary, postnatal axonal elimination is a regulated multireceptor mechanism that involves the cooperation of several muscarinic and adenosine receptor subtypes.

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Section: Discussionmentioning

confidence: 99%

Section: Relation Between Machrs and Arsmentioning

confidence: 99%

Synergistic Action of Presynaptic Muscarinic Acetylcholine Receptors and Adenosine Receptors in Developmental Axonal Competition at the Neuromuscular Junction

Nadal

García²,

Hurtado³

et al. 2016

Dev Neurosci

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“…Presynaptic adenosine receptors of type A1 and A2 are found in the terminals of the neuromusclular syn apses in skeletal muscles [1,2]. Receptors of both types are metabotropic and in the presence of endoge nous adenosine can exert opposite effects on the ace tylcholine (ACh) release: facilitating, upon activation of receptors A2A, and inhibiting, upon activation of receptors A1 [3,4].…”

Section: Introductionmentioning

confidence: 99%

The role of adenosine receptors and L-type calcium channels in the regulation of the mediator secretion in mouse motor synapses

Tarasova

Miteva

Gaidukov

et al. 2015

Biochem. Moscow Suppl. Ser. A

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The changes in spontaneous and evoked neurotransmitter release caused by agonists and antago nists of the A1 and A2A subtypes of adenosine receptors combined with inhibition of some enzymes and voltage dependent calcium channels of L type were studied in mouse diaphragm motor synapses using intra cellular microelectrode recordings of miniature endplate potentials (MEPPs) and evoked endplate potentials (EPPs). Simultaneous activation of presynaptic A1 and A2A receptors by endogenous adenosine during short term rhythmic activity of motor synapses was shown for the first time. Activation of receptors A1 pre vails and is followed by downregulation of the ACh release due to inhibition of intracellular cascade, which involves protein kinase A (PKA) and L type voltage dependent calcium channels. Activation of receptors A2A with their agonist CGS 21680 caused upregulation of the ACh secretion due to enhancement of PKA activity followed by activation of L type voltage dependent calcium channels. The mechanism of the evoked release potentiation, when A1 receptors are blocked or the activity of A2A receptors prevails over that of A1 receptors, involves calcium release from ryanodine sensitive intracellular calcium stores coupled with PKA and activation of L type voltage dependent calcium channels. It was found that protein phosphatase cal cineurin participates in downregulation of the L type voltage dependent calcium channels irrespective of the A1 receptors. It was shown for the first time that disinhibition of L type voltage dependent calcium channels caused by the calcineurin inhibition requires participation of the activity of A2A receptors and PKA. In con clusion, reciprocal interactions between presynaptic receptors A1 and A2A and their effect on the ACh release were shown in motor synapses. These interactions are mediated by the following cascade: PKA → L type volt age dependent calcium channels → ryanodine receptors of calcium stores. Final effect on the neurotrans mitter release depends on conditions of coactivation of these receptors and interplay of enzymes and L type voltage dependent calcium channels within synaptic terminals.

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“…In control conditions, the activation of adenosine A 2A and muscarinic M 1 receptors with CGS (2 nmol/L) [17,23,42] and McN (3 µmol/L) [15,16,43] increased (p < 0.05) tetanic facilitation (R value) by 9.3 ± 1.2% (n = 4; Fig. 2a) and 4.6 ± 0.8% (n = 4; Fig.…”

Section: Resultsmentioning

confidence: 97%

“…While the muscarinic M 1 -positive feedback mechanism is operative, the adenosine A 2A -receptor-mediated facilitation is suppressed. Conversely, upon increasing the levels of adenosine generated at the synapse to levels capable of activating facilitatory A 2A receptors, the M 1 -positive feedback is weakened and the muscarinic neuromodulatory control is shifted toward M 2 inhibition [17][18][19][20].…”

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confidence: 99%

Tetanic Facilitation of Neuromuscular Transmission by Adenosine A2A and Muscarinic M1 Receptors is Dependent on the Uptake of Choline via High-Affinity Transporters

Castellão-Santana¹,

Abiko²,

Ambiel³

et al. 2018

Pharmacology

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Background/Aims: In this study, we evaluated the functional impact of facilitatory presynaptic adenosine A_2A and muscarinic M₁ receptors in the recovery of neuromuscular tetanic depression caused by the blockage of high-affinity choline transporter (HChT) by hemicholinium-3 (HC-3), a condition that mimics a myasthenia-like condition. Methods: Rat diaphragm preparations were indirectly stimulated via the phrenic nerve trunk with 50-Hz frequency trains, each consisting of 500–750 supramaximal intensity pulses. The tension at the beginning (A) and at the end (B) of the tetanus was recorded and the ratio (R) B/A calculated. Results: Activation of A_2A and M₁ receptors with CGS21680 (CGS; 2 nmol/L) and McN-A-343c (McN; 3 μmol/L) increased R values. Similar facilitatory effects were obtained with forskolin (FSK; 3 μmol/L) and phorbol 12-myristate 13-acetate (PMA; 10 μmol/L), which activate adenylate cyclase and protein kinase C respectively. HC-3 (4 μmol/L) decreased transmitter exocytosis measured by real-time videomicroscopy with the FM4-64 fluorescent dye and prevented the facilitation of neuromuscular transmission caused by CGS, McN, and FSK, with a minor effect on PMA. The acetylcholinesterase inhibitor, neostigmine (NEO; 0.5 μmol/L), also decreased transmitter exocytosis. The paradoxical neuromuscular tetanic fade caused by NEO (0.5 μmol/L) was also prevented by HC-3 (4 μmol/L) and might result from the rundown of the positive feedback mechanism operated by neuronal nicotinic receptors (blocked by hexamethonium, 120 μmol/L). Conclusion: Data suggest that the recovery of tetanic neuromuscular facilitation by adenosine A_2A and M₁ receptors is highly dependent on HChT activity and may be weakened in myasthenic patients when HChT is inoperative.

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Adenosine A₁ and A_2A receptor‐mediated modulation of acetylcholine release in the mice neuromuscular junction

Cited by 35 publications

References 61 publications

Synergistic Action of Presynaptic Muscarinic Acetylcholine Receptors and Adenosine Receptors in Developmental Axonal Competition at the Neuromuscular Junction

Synergistic Action of Presynaptic Muscarinic Acetylcholine Receptors and Adenosine Receptors in Developmental Axonal Competition at the Neuromuscular Junction

The role of adenosine receptors and L-type calcium channels in the regulation of the mediator secretion in mouse motor synapses

Tetanic Facilitation of Neuromuscular Transmission by Adenosine A<sub>2A</sub> and Muscarinic M<sub>1</sub> Receptors is Dependent on the Uptake of Choline via High-Affinity Transporters

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