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Manganese inhibits ATP-induced calcium entry through the transient receptor potential channel TRPC3 in astrocytes.


Time Factors, metabolism, antagonists & inhibitors, TRPC Cation Channels, pharmacology, Pyrazoles, Microscopy, Fluorescence, Mice, Inbred C57BL, Mice, toxicity, Manganese, Diglycerides, Cells, Cultured, Cell Communication, drug effects, Calcium Signaling, Calcium Channel Blockers, Calcium, Binding, Competitive, Astrocytes, Animals, Newborn, Animals, Adenosine Triphosphate

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      Chronic exposure to elevated levels of manganese (Mn(2+)) causes neuronal injury and inflammatory activation of glia. Astrocytes selectively accumulate Mn(2+), which inhibits mitochondrial respiration and increases production of reactive oxygen species. We previously reported that sub-acute exposure to low micromolar levels of Mn(2+) in primary astrocytes inhibited ATP-induced calcium (Ca(2+)) signaling, associated with decreased levels of endoplasmic reticulum Ca(2+) and increased mitochondrial Ca(2+) loads. In the present studies, we postulated that the mechanism underlying the capacity of Mn(2+) to inhibit these purinergic signals in astrocytes could be due to competition with Ca(2+) for entry through a plasma membrane channel. These data demonstrate that acutely applied Mn(2+) rapidly inhibited ATP-induced Ca(2+) waves and transients in primary striatal astrocytes. Mn(2+) also decreased influx of extracellular Ca(2+) induced by 1-oleoyl-2-acetyl-sn-glycerol (OAG), a direct activator of the transient receptor potential channel, TRPC3. The TRPC3 inhibitor, pyrazole-3, prevented ATP- and OAG-dependent transport of Mn(2+) from extracellular stores, demonstrated by a dramatic reduction in the rate of fluorescence quenching of Fura-2. These data indicate that Mn(2+) can acutely inhibit ATP-dependent Ca(2+) signaling in astrocytes by blocking Ca(2+) entry through the receptor-operated cation channel, TRPC3. Loss of normal astrocytic responses to purinergic signals due to accumulation of Mn(2+) could therefore comprise critical homeostatic functions necessary for metabolic and trophic support of neurons. Copyright © 2012 Elsevier Inc. All rights reserved.

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