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This Article Full Text Full Text (PDF) All Versions of this Article: 560/1/157    most recent jphysiol.2004.067595v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Oliveira, L. Articles by Correia-de-Sá, P. Search for Related Content PubMed PubMed Citation Articles by Oliveira, L. Articles by Correia-de-Sá, P.

¹ Laboratório de Farmacologia/Unidade Muldidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, L. Prof. Abel Salazar, 2, 4099-003 Porto, Portugal

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 Ca²⁺ influx via ‘prevalent’ P-type or via the recruitment of ‘silent’ L-type channels. The release of [³H]ACh from rat phrenic nerve endings decreased upon increasing the stimulation frequency of the trains (750 pulses) from 5 Hz (83 ± 4 x 10³ disintegrations per minute per gram (d.p.m. g^–1); n = 11) to 50 Hz (30 ± 3 x 10³ d.p.m. g^–1; n = 5). The P-type Ca²⁺ channel blocker, -agatoxin IVA (100 nM) reduced (by 40 ± 10%; n = 6) the release of [³H]ACh evoked by 50-Hz trains, while nifedipine (1 µM, an L-type blocker) was inactive. Tetanic depression was overcome (88 ± 6 x 10³ 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, -agatoxin IVA (100 nM) failed to affect transmitter release, but nifedipine (1 µM) decreased [³H]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 [³H]ACh evoked with 50-Hz bursts. This effect was opposite to the excitatory actions of adenosine (0.5 mM), S-(p-nitrobenzyl)-6-thioinosine (5 µM, an adenosine uptake blocker) and CGS 21680C (3 nM, a selective A_2A receptor agonist); as the A₁ receptor agonist R-N⁶-phenylisopropyl adenosine (R-PIA, 300 nM) failed to affect the release of [³H]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 nM) were prevented by nifedipine (1 µM). Blocking tonic A_2A receptor activation, with ADA (0.5 U ml^–1) or 3,7-dimethyl-1-propargyl xanthine (10 µM, an A_2A antagonist), recovered -agatoxin IVA (100 nM) inhibition and caused the loss of function of nifedipine (1 µM). Data indicate that, in addition to the predominant P-type Ca²⁺ 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 Ca²⁺ influx through P- or L-type channels is likely to be mediated by endogenous adenosine. Therefore, tonic activation of presynaptic A_2A receptors operating Ca²⁺ influx via L-type channels may contribute to overcome tetanic depression during neuronal firing.

(Received 2 May 2004; accepted after revision 4 August 2004; first published online 5 August 2004)
Corresponding author P. Correia-de-Sá: Laboratório de Farmacologia, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, L. Prof Abel Salazar, 2, 4099-003 Porto, Portugal. Email: farmacol{at}icbas.up.pt

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