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Tetanic failure due to decreased endogenous adenosine A 2A tonus operating neuronal Ca v 1 (L‐type) influx in Myasthenia gravis
Author(s) -
NoronhaMatos J. B.,
Morais T.,
Trigo D.,
Timóteo M. A.,
MagalhãesCardoso M. T.,
Oliveira L.,
CorreiadeSá P.
Publication year - 2011
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2011.07216.x
Subject(s) - chemistry , nifedipine , medicine , endocrinology , acetylcholine , myasthenia gravis , adenosine , adenosine a2a receptor , motor nerve , neuromuscular junction , voltage dependent calcium channel , adenosine receptor , antagonist , receptor , pharmacology , calcium , neuroscience , biology , agonist
J. Neurochem. (2011) 117 , 797–811. Abstract In healthy motor endplates, tetanic depression is overcome by tonic adenosine A 2A ‐receptor‐mediated facilitation of transmitter release. The A 2A receptor operates a coordinated shift from fast‐desensitizing Ca v 2.1 (P/Q) calcium influx to long‐lasting Ca V 1 (L) channels on motor nerve terminals. This study aimed at investigating whether A 2A receptors‐operated Ca 2+ influx via Ca V 1 (L)‐type channels contribute to sustain acetylcholine release evoked by 50 Hz‐bursts in toxin‐induced Myasthenia gravis (TIMG) rats. In contrast to control animals, inhibition of [ 3 H]acetylcholine (ACh) release by the Ca V 2.1 (P/Q) channel blocker, ω‐Agatoxin IVA (100 nM), in TIMG rats had a higher magnitude than that observed with the Ca V 1 (L) channel blocker, nifedipine (1 μM). Adenosine deaminase (0.5 U/mL) and the A 2A receptor antagonist, ZM 241385 (50 nM), decreased [ 3 H]ACh release by a similar amount in control rats, but their effects were smaller in magnitude in myasthenic animals. The adenosine precursor, AMP (100 μM), increased (∼40%) ACh release in both control and TIMG animals. Blockade of A 2A , but not of A 1 , receptors prevented AMP‐induced facilitation of transmitter release; nifedipine (1 μM) mimicked the effect of the A 2A receptor antagonist. Video‐microscopy studies designed to measure real‐time transmitter exocytosis using the FM4‐64 fluorescent dye fully supported radiochemical data. Thus, impairment of the adaptive shift from Ca V 2.1 (P/Q) to Ca V 1 (L) channels may contribute to tetanic failure in myasthenic rats. This parallels the reduction of adenosine A 2A receptor tonus in TIMG animals, which might be restored by exogenous application of AMP.