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Journal of Neuroscience, Vol 14, 348-356, Copyright © 1994 by Society for Neuroscience
Mitochondria buffer physiological calcium loads in cultured rat dorsal root ganglion neurons
JL Werth and SA Thayer
Department of Pharmacology, University of Minnesota Medical School, Minneapolis 55455.
We sought to determine whether low-affinity, high-capacity mitochondrial
Ca2+ uptake contributes to buffering physiological Ca2+ loads in sensory
neurons. Intracellular free calcium concentration ([Ca2+]i) and
intracellular free hydrogen ion concentration ([H+]i) were measured in
single rat dorsal root ganglion (DRG) neurons grown in primary culture
using indo-1 and carboxy-SNARF-based dual emission microfluorimetry. Field
potential stimulation evoked action potential- mediated increases in
[Ca2+]. Brief trains of action potentials elicited [Ca2+]i transients that
recovered to basal levels by a single exponential process. Trains of >
25 action potentials elicited larger increases in [Ca2+]i, recovery from
which consisted of three distinct phases. During a rapid initial phase
[Ca2+]i decreased to a plateau level (450-550 nM). The plateau was followed
by a slow return to basal [Ca2+]i [Ca2+]i transients elicited by 40-50
action potentials in the presence of the mitochondrial uncoupler carbonyl
cyanide chlorophenyl hydrazone (CCCP), or the electron transport inhibitor
antimycin A1, lacked the plateau, and the recovery to basal [Ca2+]i
consisted of a single slow phase. Depolarization with 50 mM K+ produced a
multiphasic [Ca2+]i transient and increased [H+]i from 74 +/- 3 to 107 +/-
8 nM. The rise in [H+]i was dependent upon extracellular Ca2+ and was
inhibited by mitochondrial poisons. With mitochondrial Ca2+ buffering
pharmacologically blocked, the recovery to basal [Ca2+]i was unaffected by
removal of extracellular Na+. We conclude that large Ca2+ loads are
initially buffered by fast mitochondrial sequestration that effectively
uncouples electron transport from ATP synthesis, leading to an increase in
[H+]i. Small Ca2+ loads are buffered by a nonmitochondrial, Na(+)-
independent process.
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