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The Journal of Neuroscience, August 15, 2002, 22(16):6962-6971

Mitochondrial Ca²⁺ Uptake Regulates the Excitability of Myenteric Neurons

Pieter Vanden Berghe, James L. Kenyon, and Terence K. Smith

Department of Physiology and Cell Biology, University of Nevada, School of Medicine, Reno, Nevada 89557-0046

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 ~15 sec. Exposure to the protonophore carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP; 1 µM) 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 µM) had similar effects that developed more slowly. Depletion of the intracellular Ca²⁺ stores with thapsigargin (2 µM) or ryanodine (10 µM) 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 µM) 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.

Key words: mitochondria; fura-2; intracellular calcium; MitoTracker; ER tracker; neuron; K_Ca channel; K_ATP channel; afterhyperpolarization; neuronal excitability; antimycin A; FCCP; rotenone; oligomycin; guinea pig ileum

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22166962-10$05.00/0

This article has been cited by other articles:

				D. T. W. Chang, A. S. Honick, and I. J. Reynolds Mitochondrial trafficking to synapses in cultured primary cortical neurons. J. Neurosci., June 28, 2006; 26(26): 7035 - 7045. [Abstract] [Full Text] [PDF]

				P. V. Berghe, G. W. Hennig, and T. K. Smith Characteristics of intermittent mitochondrial transport in guinea pig enteric nerve fibers Am J Physiol Gastrointest Liver Physiol, April 1, 2004; 286(4): G671 - G682. [Abstract] [Full Text] [PDF]

				S. H. Kang, P. Vanden Berghe, and T. K. Smith Ca2+-activated Cl- current in cultured myenteric neurons from murine proximal colon Am J Physiol Cell Physiol, April 1, 2003; 284(4): C839 - C847. [Abstract] [Full Text] [PDF]

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