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Freestone PS, Chung KK, Guatteo E, Mercuri NB, Nicholson LF, Lipski J: Acute action of rotenone on nigral dopaminergic neurons--involvement of reactive oxygen species and disruption of Ca2+ homeostasis. Eur J Neurosci. 2009 Nov;30(10):1849-59. Epub 2009 Nov 11.
Rotenone is a toxin used to generate animal models of Parkinson's disease; however, the mechanisms of toxicity in substantia nigra pars compacta (SNc) neurons have not been well characterized. We have investigated rotenone (0.05-1 microm) effects on SNc neurons in acute rat midbrain slices, using whole-cell patch-clamp recording combined with microfluorometry. Rotenone evoked a tolbutamide-sensitive outward current (94 +/- 15 pA) associated with increases in intracellular [Ca (2+)] ([Ca (2+)](i)) (73.8 +/- 7.7 nm) and intracellular [Na (+)] (3.1 +/- 0.6 mm) (all with 1 microm). The outward current was not affected by a high ATP level (10 mm) in the patch pipette but was decreased by Trolox. The [Ca (2+)](i) rise was abolished by removing extracellular Ca (2+), and attenuated by Trolox and a transient receptor potential M2 (TRPM2) channel blocker, N-(p-amylcinnamoyl) anthranilic acid. Other effects included mitochondrial depolarization (rhodamine-123) and increased mitochondrial reactive oxygen species (ROS) production (MitoSox), which was also abolished by Trolox. A low concentration of rotenone (5 nm) that, by itself, did not evoke a [Ca (2+)](i) rise resulted in a large (46.6 +/- 25.3 nm) Ca (2+) response when baseline [Ca (2+)](i) was increased by a 'priming' protocol that activated voltage-gated Ca (2+) channels. There was also a positive correlation between 'naturally' occurring variations in baseline [Ca (2+)](i) and the rotenone-induced [Ca (2+)](i) rise. This correlation was not seen in non-dopaminergic neurons of the substantia nigra pars reticulata (SNr). Our results show that mitochondrial ROS production is a key element in the effect of rotenone on ATP-gated K (+) channels and TRPM2-like channels in SNc neurons, and demonstrate, in these neurons (but not in the SNr), a large potentiation of rotenone-induced [Ca (2+)](i) rise by a small increase in baseline [Ca (2+)](i). |
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