2',3'-Dideoxycytidine alters calcium buffering in cultured dorsal root ganglion neurons.
Mitochondria play a prominent role in shaping intracellular calcium concentration ([Ca2+]i) transients in dorsal root ganglion neurons. Mitochondrial DNA polymerase is inhibited by antiviral compounds such as 2',3'-dideoxycytidine (ddC). Here, we test the hypothesis that ddC can alter mitochondrially mediated Ca2+ buffering in neurons. Chronic treatment of dorsal root ganglion cultures with ddC (1 microM) lowered mitochondrial DNA levels and decreased the mitochondrially mediated component of depolarization-induced [Ca2+]i transients. The inhibition increased in a time-dependent manner, reaching a maximum at 6 days. ddC did not affect small, action potential-evoked, [Ca2+]i transients that are predominantly buffered by Ca(2+)-ATPases, suggesting that ATP levels were not depleted. The drug did not inhibit whole-cell Ca2+ currents, indicating that the Ca2+ load was not affected. Thus, ddC produces a graded, time-dependent inhibition of mitochondrial function that is reflected, in part, by a decrease in the direct buffering of Ca2+ by mitochondria. This effect may contribute to the peripheral neuropathy that results from ddC treatment. Furthermore, ddC promises to be a useful tool to study the role of mitochondria in [Ca2+]i homeostasis and neurodegenerative processes.
Department of Pharmacology, University of Minnesota Medical School, Minneapolis 55455.
J L
JL
Werth
B
B
Zhou
L M
LM
Nutter
S A
SA
Thayer
D000818:Animals; D002021:Buffers; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000096:biosynthesis; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008564:Membrane Potentials; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016047:Zalcitabine / Q000494:pharmacology*
D002021:Buffers; D004272:DNA, Mitochondrial; D016047:Zalcitabine; D002118:Calcium