Impairment of the adaptive shift from CAv2.1 (p/q type) to CAv1 (L-type)
channels contributes to tetanic failure in myasthenia
gravis: On the role of adenosine A2A receptors
-
1
Universidade do Porto, Laboratorio de Farmacologia e Neurobiologia, UMIB, Instituto de Ciencias Biomedicas de Abel Salazar (ICBAS), Portugal
During short stimulation trains, CaV2.1 (P/Q) channels clustered at active zones control nerve-evoked acetylcholine (ACh) release from motor nerve terminals. During high frequency neuronal firing, there is a shift in Ca2+ dynamics from CaV2.1 (P/Q) to CaV1 (L) subtype channels, which is co-ordinated by endogenous adenosine acting via facilitatory A2A receptors (Oliveira et al., 2004, J. Physiol., 560, 157-168). On the basis of this mechanism, we investigated whether this could be observed using a rat model of Myasthenia gravis induced by α-bungarotoxin (TIMG).The procedures used for measuring [3H]ACh release were previously described (Correia-de-Sá et al., 1996, J. Neurophysiol., 79, 3910-19). Exocytosis was monitored using the membrane-selective FM4-64 fluorescent dye. Transmitter release was evoked by phrenic nerve stimulation with either 5 Hz-trains (750 pulses) or 50 Hz-bursts.
In control animals, ω-agatoxin IVA (100 nM, a CaV2.1 (P/Q) channel blocker) reduced by 21±4% (n=4) the release of [3H]ACh evoked by 5 Hz-trains, while nifedipine (1 μM, an CaV1 (L) channel blocker) was inactive. At 50 Hz-bursts, ω-agatoxin IVA (100 nM) had no effect, but nifedipine (1 μM) decreased [3H]ACh release by 21±7% (n=4). The predominance of CaV2.1 (P/Q type) currents during 5 Hz-trains and the recruitment of CaV1 (L-type) channels during 50 Hz-bursts was confirmed in real-time experiments by monitoring FM4-64 destaining as a measure of transmitter exocytosis. The co-ordinated shift from CaV2.1 (P/Q) to CaV1 (L) channels disappeared in TIMG animals, i.e. ω-Agatoxin IVA (100 nM) reduced by 78±3% (n=6) and 35±6% (n=6) the release of [3H]ACh release evoked with 5-Hz trains and 50-Hz bursts, respectively, while nifedipine (1 μM) was ineffective. TIMG animals’ exhibit reduced adenosine A2A receptor tonus particularly during 50 Hz- bursts. This was evidenced because the inhibitory effects of adenosine deaminase (ADA, 2.5 U/ml) and ZM241385 (50 nM, an A2A receptor antagonist) were significantly (P<0.05) attenuated in TIMG animals as compared to controls. Likewise, changes in FM4-46 destaining were almost prevented in TIMG animals in the presence of ZM241385 (50 nM).
The results suggests that impairment of the adaptive shift from fast desensitizing CaV2.1 (P/Q) to long lasting CaV1 (L) channels might contribute to tetanic failure of neurotransmission in myasthenic patients. This correlates well with the reduced adenosine A2A receptor tonus observed in myasthenics.
This work was supported by FCT and UMIB-215/94.
Conference:
11th Meeting of the Portuguese Society for Neuroscience, Braga, Portugal, 4 Jun - 6 Jun, 2009.
Presentation Type:
Poster Presentation
Topic:
Neuronal Communication
Citation:
Noronha-Matos
JB,
Morais
T,
Trigo
D,
Timoteo
MA,
Oliveira
L and
Correia-de-Sa
P
(2009). Impairment of the adaptive shift from CAv2.1 (p/q type) to CAv1 (L-type)
channels contributes to tetanic failure in myasthenia
gravis: On the role of adenosine A2A receptors.
Front. Neurosci.
Conference Abstract:
11th Meeting of the Portuguese Society for Neuroscience.
doi: 10.3389/conf.neuro.01.2009.11.150
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Received:
12 Aug 2009;
Published Online:
12 Aug 2009.
*
Correspondence:
J. B Noronha-Matos, Universidade do Porto, Laboratorio de Farmacologia e Neurobiologia, UMIB, Instituto de Ciencias Biomedicas de Abel Salazar (ICBAS), Porto, Portugal, bernardonm@gmail.com