TY - JOUR
T1 - Mitochondrial Ca2+ uptake prevents desynchronization of quantal release and minimizes depletion during repetitive stimulation of mouse motor nerve terminals
AU - David, Gavriel
AU - Barett, Ellen F.
N1 - Copyright:
Copyright 2004 Elsevier Science B.V., Amsterdam. All rights reserved.
PY - 2003/4/15
Y1 - 2003/4/15
N2 - We investigated how inhibition of mitochondrial Ca2+ uptake affects transmitter release from mouse motor terminals during brief trains of action potentials (500 at 50 Hz) in physiological bath [Ca2+]. When mitochondrial Ca2+ uptake was inhibited by depolarizing mitochondria with antimycin A1 or carbonyl cyanide m-chlorophenyl-hydrazone, the stimulation-induced increase in cytosolic [Ca2+] was greater (> 10 μM, compared to ≤ 1μM in control solution), the quantal content of the endplate potential (EPP) depressed more rapidly (∼84% depression compared to ∼8% in controls), and asynchronous release during the stimulus train reached higher frequencies (peak rates of ∼6000 s-1 compared to ∼75 s-1 in controls). These effects of mitochondrial depolarization were not accompanied by a significant change in EPP quantal content or the rate of asynchronous release during 1 Hz stimulation, and were not seen in oligomycin, which blocks mitochondrial ATP synthesis without depolarizing mitochondria. Inhibition of endoplasmic reticular Ca2+ uptake with cyclopiazonic acid also had little effect on stimulation-induced changes in cytosolic [Ca2+] or EPP amplitude. We hypothesize that the high rate of asynchronous release evoked by stimulation during mitochondrial depolarization was produced by the elevation of cytosolic [ Ca2+], and contributed to the accelerated depression of phasic release by reducing the availability of releasable vesicles. During mitochondrial depolarization, the post-tetanic potentiation of the EPP observed under control conditions was replaced by a post-tetanic depression with a slow time course of recovery. Thus, mitochondrial Ca2+ uptake is essential for sustaining phasic release, and thus neuromuscular transmission, during and following tetanic stimulation.
AB - We investigated how inhibition of mitochondrial Ca2+ uptake affects transmitter release from mouse motor terminals during brief trains of action potentials (500 at 50 Hz) in physiological bath [Ca2+]. When mitochondrial Ca2+ uptake was inhibited by depolarizing mitochondria with antimycin A1 or carbonyl cyanide m-chlorophenyl-hydrazone, the stimulation-induced increase in cytosolic [Ca2+] was greater (> 10 μM, compared to ≤ 1μM in control solution), the quantal content of the endplate potential (EPP) depressed more rapidly (∼84% depression compared to ∼8% in controls), and asynchronous release during the stimulus train reached higher frequencies (peak rates of ∼6000 s-1 compared to ∼75 s-1 in controls). These effects of mitochondrial depolarization were not accompanied by a significant change in EPP quantal content or the rate of asynchronous release during 1 Hz stimulation, and were not seen in oligomycin, which blocks mitochondrial ATP synthesis without depolarizing mitochondria. Inhibition of endoplasmic reticular Ca2+ uptake with cyclopiazonic acid also had little effect on stimulation-induced changes in cytosolic [Ca2+] or EPP amplitude. We hypothesize that the high rate of asynchronous release evoked by stimulation during mitochondrial depolarization was produced by the elevation of cytosolic [ Ca2+], and contributed to the accelerated depression of phasic release by reducing the availability of releasable vesicles. During mitochondrial depolarization, the post-tetanic potentiation of the EPP observed under control conditions was replaced by a post-tetanic depression with a slow time course of recovery. Thus, mitochondrial Ca2+ uptake is essential for sustaining phasic release, and thus neuromuscular transmission, during and following tetanic stimulation.
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U2 - 10.1113/jphysiol.2002.035196
DO - 10.1113/jphysiol.2002.035196
M3 - Article
C2 - 12588898
AN - SCOPUS:0038414654
VL - 548
SP - 425
EP - 438
JO - Journal of Physiology
JF - Journal of Physiology
SN - 0022-3751
IS - 2
ER -