2',3'-Dideoxycytidine alters calcium buffering in cultured dorsal root ganglion neurons

J. L. Werth, B. Zhou, L. M. Nutter, Stanley A Thayer

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

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 μM) 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 Ca2+-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.

Original languageEnglish (US)
Pages (from-to)1119-1124
Number of pages6
JournalMolecular Pharmacology
Volume45
Issue number6
StatePublished - 1994

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