Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 425-438 |
| Number of pages | 14 |
| Journal | Journal of Physiology |
| Volume | 548 |
| Issue number | 2 |
| DOIs | |
| State | Published - Apr 15 2003 |
Fingerprint
ASJC Scopus subject areas
- Physiology
Cite this
Mitochondrial Ca2+ uptake prevents desynchronization of quantal release and minimizes depletion during repetitive stimulation of mouse motor nerve terminals. / David, Gavriel; Barrett, Ellen.
In: Journal of Physiology, Vol. 548, No. 2, 15.04.2003, p. 425-438.Research output: Contribution to journal › Article
}
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 - Barrett, Ellen
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.
UR - http://www.scopus.com/inward/record.url?scp=0038414654&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0038414654&partnerID=8YFLogxK
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 -