Premium
Tetanic depression is overcome by tonic adenosine A 2A receptor facilitation of L‐type Ca 2+ influx into rat motor nerve terminals
Author(s) -
Oliveira Laura,
Timóteo M. Alexandrina,
CorreiadeSá Paulo
Publication year - 2004
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2004.067595
Subject(s) - adenosine , nifedipine , acetylcholine , excitatory postsynaptic potential , motor nerve , chemistry , phrenic nerve , neuromuscular junction , neuromuscular transmission , free nerve ending , medicine , endocrinology , biophysics , anesthesia , calcium , neuroscience , biology , receptor , biochemistry , respiratory system
Motor nerve terminals possess multiple voltage‐sensitive calcium channels operating acetylcholine (ACh) release. In this study, we investigated whether facilitation of neuromuscular transmission by adenosine generated during neuronal firing was operated by Ca 2+ influx via ‘prevalent’ P‐type or via the recruitment of ‘silent’ L‐type channels. The release of [ 3 H]ACh from rat phrenic nerve endings decreased upon increasing the stimulation frequency of the trains (750 pulses) from 5 Hz (83 ± 4 × 10 3 disintegrations per minute per gram (d.p.m. g −1 ); n = 11) to 50 Hz (30 ± 3 × 10 3 d.p.m. g −1 ; n = 5). The P‐type Ca 2+ channel blocker, ω‐agatoxin IVA (100 n m ) reduced (by 40 ± 10%; n = 6) the release of [ 3 H]ACh evoked by 50‐Hz trains, while nifedipine (1 μ m , an L‐type blocker) was inactive. Tetanic depression was overcome (88 ± 6 × 10 3 d.p.m. g −1 ; n = 12) by stimulating the phrenic nerve with 50‐Hz bursts (five bursts of 150 pulses, 20 s interburst interval). In these conditions, ω‐agatoxin IVA (100 n m ) failed to affect transmitter release, but nifedipine (1 μ m ) decreased [ 3 H]ACh release by 21 ± 7% ( n = 4). Inactivation of endogenous adenosine with adenosine deaminase (ADA, 0.5 U ml −1 ) reduced (by 54 ± 8%, n = 5) the release of [ 3 H]ACh evoked with 50‐Hz bursts. This effect was opposite to the excitatory actions of adenosine (0.5 m m ), S ‐( p ‐nitrobenzyl)‐6‐thioinosine (5 μ m , an adenosine uptake blocker) and CGS 21680C (3 n m , a selective A 2A receptor agonist); as the A 1 receptor agonist R ‐ N 6 ‐phenylisopropyl adenosine (R‐PIA, 300 n m ) failed to affect the release of [ 3 H]ACh, the results indicate that adenosine generated during 50‐Hz bursts exerts an A 2A ‐receptor‐mediated tonus. The effects of ADA (0.5 U ml −1 ) and CGS 21680C (3 n m ) were prevented by nifedipine (1 μ m ). Blocking tonic A 2A receptor activation, with ADA (0.5 U ml −1 ) or 3,7‐dimethyl‐1‐propargyl xanthine (10 μ m , an A 2A antagonist), recovered ω‐agatoxin IVA (100 n m ) inhibition and caused the loss of function of nifedipine (1 μ m ). Data indicate that, in addition to the predominant P‐type Ca 2+ current triggering ACh release during brief tetanic trains, motoneurones possess L‐type channels that may be recruited to facilitate transmitter release during high‐frequency bursts. The fine‐tuning control of Ca 2+ influx through P‐ or L‐type channels is likely to be mediated by endogenous adenosine. Therefore, tonic activation of presynaptic A 2A receptors operating Ca 2+ influx via L‐type channels may contribute to overcome tetanic depression during neuronal firing.