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Vanden Berghe P, Kenyon JL, Smith TK: Mitochondrial Ca2+ uptake regulates the excitability of myenteric neurons. . J Neurosci. 2002 Aug 15;22(16):6962-71.
We investigated the role of mitochondria in the regulation of intracellular Ca2+ ([Ca2+] i) and excitability of myenteric neurons in guinea pig ileum, using microelectrodes and fura-2 [Ca2+] i measurements. In AH/Type-II neurons, action potentials evoke ryanodine-sensitive increases in [Ca2+] i that activate Ca2+-dependent K+ channels and slow afterhyperpolarizations (AH) lasting approximately 15 sec. Exposure to the protonophore carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP; 1 microm) had no significant effect on the membrane potential or resting [Ca2+] i. However, action potentials elicited in the presence of FCCP triggered a sustained (> 5 min) increase in [Ca2+] i and a compound hyperpolarization (13.4 +/- 1.5 mV). The respiratory chain blockers antimycin A and rotenone (10 microm) had similar effects that developed more slowly. Depletion of the intracellular Ca2+ stores with thapsigargin (2 microm) or ryanodine (10 microm) greatly attenuated the hyperpolarization caused by FCCP. S/Type-I neurons that do not have AH were hyperpolarized by mitochondrial inhibition independently of action potentials. Blockade of the F0F1 ATPase by oligomycin (10 microm) had variable effects on myenteric neurons. The majority of AH/Type-II neurons were hyperpolarized by oligomycin, most likely by activating ATP-dependent K+ channels. This hyperpolarization was not triggered by action potential firing and not accompanied by an increase in [Ca2+] i. MitoTracker staining revealed a dense mitochondrial network particularly in myenteric AH/Type-II neurons, supporting the importance of mitochondrial Ca2+ buffering in this subset of neurons. The data indicate that mitochondrial uptake of Ca2+ released from the endoplasmic reticulum sets [Ca2+] i and the activity of Ca2+-dependent conductances, thus regulating the excitability of myenteric neurons. |
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